Cardiovascular Diseases

Chapter 3
 

Cardiovascular Diseases
 

Introduction 363
 

Conclusions of Previous Surgeon General’s Reports 363
 

Biologic Basis 364
 

Smoking, Atherogenesis, and Thrombosis 364
 

Smoking and Endothelial Injury or Endothelial Dysfunction 365
 

Smoking and Thrombosis/Fibrinolysis 367
 

Smoking and Inflammation 368
 

Smoking, Lipids, and Lipid Metabolism 368
 

Smoking and Cardiovascular Function 369
 

Smoking and Increased Oxygen Demand 369
 

Smoking, Decreased Oxygen Supply, and Increased Blood Rheology 369
 

Summary 371
 

Smoking and Subclinical Atherosclerosis 371
 

Epidemiologic Evidence 371
 

Evidence Synthesis 379
 

Conclusion 379
 

Implications 379
 

Smoking, Coronary Heart Disease, and Sudden Death 384
 

Epidemiologic Evidence 384
 

Coronary Heart Disease 384
 

Sudden Death 387
 

Congestive Heart Failure 387
 

Evidence Synthesis 392
 

Conclusions 392
 

Implications 392
 

Smoking and Cerebrovascular Disease 393
 

Epidemiologic Evidence 394
 

Evidence Synthesis 395
 

Conclusion 395
 

Implication 395
 

Smoking and Abdominal Aortic Aneurysm 396
 

Epidemiologic Evidence 396
 

Evidence Synthesis 397
 

Conclusion 397
 

Implication 397

 361 
Chapter 3

Surgeon General’s Report 

Summary 397
 

Conclusions 407
 

References 408
 

362 
The Health Consequences of Smoking 

Introduction 

Heart disease and stroke—the main types of car- failure (CHF), and other conditions. Nearly 950,000 

diovascular disease caused by smoking—are the first Americans die each year as a result of CVD, accountand third leading causes of death in the United States, ing for 39.4 percent of all deaths in 2000 (AHA 2002). 

respectively (American Heart Association [AHA] 2002; This chapter reviews the evidence on the relationship 

Anderson 2002). More than 61 million people in the between smoking and CVD. In particular, it examines 

United States suffer from some form of cardiovascu- the associations between smoking and subclinical 

lar disease (CVD), including high blood pressure, atherosclerosis, CHD and sudden death, stroke, and 

coronary heart disease (CHD), stroke, congestive heart abdominal aortic aneurysm (AAA). 

Conclusions of Previous Surgeon General’s Reports 

One of the first topics addressed in the Surgeon 

General’s reports was smoking and CVD, although the 

1964 report focused primarily on the relationships between smoking and respiratory diseases, including 

cancer and chronic lung diseases (U.S. Department of 

Health, Education, and Welfare [USDHEW] 1964). The 

report noted that male cigarette smokers had higher 

death rates from CHD than nonsmoking males. In 

1967, the second Surgeon General’s report on smoking concluded that the evidence “strongly suggests that 

cigarette smoking can cause death from coronary artery disease” (USDHEW 1967, p. 27). With a growing 

number of studies addressing other cardiovascular 

endpoints, the 1971 and 1974 reports highlighted the 

associations between smoking and peripheral vascular disease, aortic atherosclerosis, and cerebrovascular disease, including stroke (USDHEW 1971, 1974). 

The 1979 report concluded that smoking was not only 

one of the main risk factors for CHD (nonfatal and fatal myocardial infarctions [MIs] and sudden death), 

but was a causal factor supported by evidence considered to be proved beyond a “reasonable doubt” 

(USDHEW 1979, p. 4-63). In addition, that report presented evidence of strong associations with morbidity 

from peripheral vascular disease and aortic aneurysms. 

In contrast, the association between smoking and 

stroke was considered “not conclusive” (USDHEW 

1979, p. 1-14). 

Subsequent Surgeon General’s reports reviewed 

the evidence linking cigarette smoking to CHD. The 

conclusions in the 1983 Surgeon General’s report 

reaffirmed that cigarette smoking is one of the major 

independent causes of CHD and, given the prevalence 

of smoking, “should be considered the most important of the known modifiable risk factors for coronary 

heart disease” (U.S. Department of Health and Human 

Services [USDHHS] 1983, p. iv). The evidence considered included a large number of epidemiologic, 

clinical, and experimental studies carried out with a 

variety of methods and research designs. Until the 

1980s, though, there had been limited evidence related 

to the reduction of risk after maintained cessation. In 

an extensive review of updated data on the benefits to 

cardiovascular health from smoking cessation, the 1990 

Surgeon General’s report found that “smoking cessation reduces the risk of both ischemic stroke and subarachnoid hemorrhage compared with continued 

smoking” (USDHHS 1990, p. 11). Other conclusions 

from that report include the following: 

The excess risk of CHD caused by smoking is 

reduced by about half after 1 year of smoking 

abstinence and then declines gradually. After 

15 years of abstinence, the risk of CHD is similar to that of persons who have never smoked. 

Among persons with diagnosed CHD, smoking cessation markedly reduces the risk of recurrent infarction and cardiovascular death. 

In many studies, this reduction in risk of 

recurrence or premature death has been 50 percent or more. 

Cardiovascular Diseases 363 
Surgeon General’s Report 

Smoking cessation substantially reduces the 

risk of peripheral artery occlusive disease compared with continued smoking. 

Among patients with peripheral artery disease, smoking cessation improves exercise tolerance, reduces the risk of amputation after 

peripheral artery surgery, and increases overall survival (USDHHS 1990, p. 260). 

The 1998 Surgeon General’s report focused on the 

impact of smoking in ethnic and racial minority populations in the United States (USDHHS 1998) and concluded that even though more data would be helpful, 

existing data indicated that the association of tobacco 

use with CHD did not differ between whites and four 

major racial and ethnic minority groups. A similar conclusion was reached for women in the 2001 Surgeon 

General’s report on women and smoking (USDHHS 

2001). 

This chapter is not an exhaustive review of the 

now vast literature on tobacco smoking and heart and 

vascular disease, although it does include an update 

of recent clinical and epidemiologic studies on the subject. The primary focus, however, is a review of the 

evidence relevant to smoking and subclinical measures 

of atherosclerosis, including what is understood about 

the role of smoking in the pathophysiologic processes 

that cause atherosclerosis and its clinical manifestations (i.e., CVD syndromes including coronary artery 

disease, AAA, peripheral vascular disease, and stroke). 

These advances in understanding of pathogenesis 

deepen the understanding of smoking as a cause of 

CVD. 

Search strategies for this chapter included 

reviewing previous Surgeon General’s reports on 

smoking, publications originating from the largest 

observational studies on CVD, and reference lists from 

important publications; consulting with content experts; and conducting focused literature searches on 

specific topics including the new literature on subclinical measures. 

Biologic Basis 

When the association between cigarette smoking 

and CVD was first identified in epidemiologic studies, the underlying biologic mechanisms were not yet 

well understood. The injury hypothesis of atherosclerosis, formally proposed in the mid-1970s (Ross and 

Glomset 1976a,b), provided a framework for considering the atherosclerotic effects of smoking, even 

though the specific tobacco components and the precise mechanisms for the injury to the endothelium (the 

inner cellular layer of the arterial wall) were unknown. 

During the 1990s, research further clarified the pathophysiology of the atherosclerotic effects of cigarette 

smoking. In addition, in the last three decades a large 

body of evidence has accumulated, demonstrating that 

smoking increases the risk for thrombosis (USDHHS 

1990; Meade et al. 1993; Miller et al. 1998). This evidence provides an additional framework for understanding the pathophysiologic effects of smoking on 

the basic underlying processes of CVD. Recent experimental work, including in vitro studies, animal studies, and controlled experiments in humans, has added 

to the understanding of these mechanisms. This evidence is reviewed in the following section. 

Smoking, Atherogenesis, and Thrombosis 

The development of atherosclerosis is the main 

underlying pathophysiologic process of the most clinically significant manifestations of CVD, namely CHD, 

stroke (cerebrovascular disease), and peripheral arterial disease. Atherosclerosis is a process of hardening 

of the arteries characterized by deposition of lipid in 

the inner layers of the arteries, by fibrosis, and by thickening of the arterial wall. Atherosclerotic plaques develop over time, slowly progressing from the early 

lipid deposition that characterizes fatty streaks, 

through the more advanced raised fibrous lesions that 

decrease the space inside the artery (the arterial 

lumen), to the complicated lesions that are usually associated with clinical events. The process of plaque destabilization and complications is thought to be associated with inflammatory changes and thrombotic 

complications that obstruct the blood flow and result 

in clinical manifestations such as MI or stroke. There 

are underlying complex interactions of the blood 

(serum and blood cells) with the arterial wall as well 

as between cellular elements within the arterial wall 

itself. Table 3.1 offers a basic summary of the stages 

364 Chapter 3 
The Health Consequences of Smoking 

Table 3.1 Basic pathogenic mechanisms in atherogenesis 

Stage of change	 Mechanism 

Interactions between blood components 

and the arterial wall (endothelium) 

Hypercholesterolemia (increased low-density lipoprotein 

[LDL] cholesterol) 

Endothelial dysfunction 

Leukocyte and platelet activation and adherence to the 

endothelium 

Migration of leukocytes through the endothelium 

Changes within the arterial wall LDL modification (oxidation) 

LDL accumulation in monocytes, turning them into foam cells 

Accumulation of LDL and collagen in intercellular space 

Smooth muscle cell proliferation 

Advanced changes, complications Plaque inflammation 

Endothelial denudation 

Platelet activation, micro- and macro-thrombosis 

Fibrinolysis of thrombi 

Plaque/thrombi rupture—emboli 

and related mechanisms of the complex multistage 

phenomenon of atherogenesis. Each of these processes 

is mediated by a variety of chemotactic molecules and 

cytokines (Ross 1993, 1999). 

The following section presents evidence showing that cigarette smoking affects a number of these 

processes. The evidence demonstrates that this delicate and highly regulated physiologic interface between blood and arterial wall components is adversely 

and strongly affected by the toxic products added to 

the bloodstream from cigarette smoke. These toxins 

then become part of the complex atherothrombotic 

process underlying CVD (Powell 1998). 

Smoking and Endothelial Injury 

or Endothelial Dysfunction 

The critical role of endothelial dysfunction in the 

early stages of atherosclerosis is now well recognized 

(Ross 1993, 1999). Endothelial dysfunction is associated with an increased adhesion of circulating monocytes and T lymphocytes to the endothelium as well 

as with their subsequent migration into the intimal 

layer of the arterial wall, the layer of cells and tissue 

innermost to the arterial wall. These cells, in the presence of modified low-density lipoprotein (LDL) cholesterol (e.g., oxidized LDL cholesterol), become foam 

cells and accumulate in the intima, constituting a key 

element in the early phases of atherogenesis. Endothelial dysfunction has been experimentally linked to 

atherosclerosis in animal models (Moore 1973) as well 

as in humans (Celermajer et al. 1992; Corretti et al. 

1995). 

Early reports on the possible detrimental effects 

of cigarette smoking on the endothelium focused 

mainly on morphologic changes in the endothelium 

(Pittilo 1990; USDHHS 1990). This research included 

animals experimentally exposed to nicotine at serum 

levels similar to those of human smokers, and observational and experimental human studies. The findings included the following: 

•	 Umbilical arteries from cords of infants born to 

smoking mothers showed endothelial changes 

absent in cords from nonsmoking mothers 

(Asmussen and Kjeldsen 1975; Asmussen 1982a,b; 

Pittilo 1990). These changes included subendothelial edema or swelling, widening of the intercellular junctions between cells, distension of the 

endoplasmic reticulum, and increased numbers of 

mitochondria. Similarly, morphologic examinations of uterine arteries in smoking women 

showed significantly more inter- and intracellular 

holes in the endothelium than did arteries in nonsmoking women (Bylock et al. 1979). 

Cardiovascular Diseases 365 
Surgeon General’s Report 

•	 Short-term experimental studies in healthy nonsmokers demonstrated that cigarette smoking is 

associated with an acute increase in the endothelial cell count in circulating blood. Compared with 

the minimal effects of nontobacco cigarettes, smoking two tobacco cigarettes more than doubled the 

number of damaged endothelial cells (anuclear 

carcasses) in the circulating blood of healthy persons (Davis et al. 1985). This effect was not modified by the previous administration of aspirin or 

rutosides (semisynthetic derivatives of rutin, a 

naturally occurring flavonoid) (Davis et al. 1986, 

1989). 

•	 Other laboratory data support the biologic plausibility of the above effects: cultured rat peritoneal mesothelial cells were exposed to plasma 

obtained from nonsmoking persons and from persons who had just smoked two cigarettes (Pittilo 

et al. 1985). Whereas the plasma from nonsmokers had little effect on the cultured cells, the plasma 

from smokers produced marked morphologic alterations, including blebbing or bubble formation 

of the luminal membrane. Pittilo and colleagues 

(1984) reported that exposure of rat endothelium 

to the blood from a person who had recently 

smoked two cigarettes resulted in the deposition 

of large numbers of platelets on the endothelial 

surface, an effect that was not observed when exposing the endothelium to human blood obtained 

before smoking. Likewise, in the absence of morphologic changes, cigarette smoke exposure in 

dogs resulted in an increased endothelial permeability to the coagulable protein fibrinogen (Allen 

et al. 1988). Pittilo (1990) reviewed animal studies 

that further supported these observations. A number of experiments with rabbit and rat models conducted during the 1980s consistently found that 

cigarette smoking was associated with morphologic changes in the endothelium, including cell 

loss and the formation of blebs and microvillouslike projections into the luminal cell surfaces. 

In recent years, more subtle functional changes 

in the endothelium have been associated with smoking. Even in the absence of morphologic changes, a 

dysfunctional endothelium can secrete growth factors, 

chemotactic molecules that draw in inflammatory cells, 

and cytokines that stimulate the inflammatory process 

of atherosclerosis. The cytokines and other molecules 

can stimulate smooth muscle cell proliferation, 

monocyte/lymphocyte adhesion, and subendothelial 

migration leading to atherosclerosis and the loss of the 

endothelium’s normal antithrombotic properties 

(Pittilo 1990; Vogel 1997; Hutchison 1998). 

The endothelium regulates the vascular tone by 

secreting vasodilators (e.g., nitric oxide) and vasoconstrictors (Arnal et al. 1999). The functional status of 

the endothelium can be studied by examining arterial 

diameter changes in response to stimuli whose effects 

depend on the integrity of the endothelium. Quantitative angiography, for example, can measure changes 

in the coronary artery diameter in response to varying 

concentrations of acetylcholine, an endotheliumdependent vasodilator. Plethysmography can record 

changes in the diameter of the brachial artery in response to stimuli from an endothelium-dependent 

vasodilator (e.g., reactive hyperemia induced by blood 

flow increase) by measuring the pressure or by ultrasound (Celermajer et al. 1992; Corretti et al. 1995). Using these techniques, young and middle-aged cigarette 

smokers without disease had a significant reduction 

in endothelium-dependent vasodilatation compared 

with nonsmoking controls (Celermajer et al. 1993). This 

association was dose-dependent (vasodilatation decreased with more pack-years 1 of exposure) and 

seemed to be potentially reversible (a weaker association was observed in former smokers). Similar effects 

were seen in young persons who reported exposures 

to secondhand smoke, also in a dose-dependent fashion (Celermajer et al. 1996). Further studies have 

confirmed these findings and suggest a synergism between smoking and hypercholesterolemia (Heitzer 

et al. 1996), raising the possibility that smoking potentiates endothelial dysfunction by enhancing LDL 

oxidation. 

Clinical studies that used measures of endothelial dysfunction in the coronary arteries have also confirmed these results. For example, a 1999 report 

showed that smokers had no increases in coronary 

myocardial blood flow (measured with positron emission tomography) in response to a cold pressor test 

(Campisi et al. 1999). However, after administration 

of L-arginine (the precursor of nitric oxide), the myocardial blood flow response in smokers normalized, 

becoming indistinguishable from that of nonsmokers. 

This observation suggests that the abnormal flow 

response in smokers is related to endothelial dysfunction (Campisi et al. 1999). Further evidence of the 

deleterious effects of smoking on endothelial function 

1

Pack-years = The number of years of smoking multiplied by the number of packs of cigarettes smoked per day. 

366 Chapter 3 
The Health Consequences of Smoking 

comes from human experiments showing steady increases in the von Willebrand factor (vWF), a possible 

marker of endothelial damage, 10 and 30 minutes after smoking two cigarettes (Blann et al. 1998). Compared with nonsmokers, smokers also released smaller 

amounts of tissue plasminogen activator (TPA) when 

stimulated by substance P, suggesting another mechanism whereby endothelial cell dysfunction may increase thrombosis (Newby et al. 1999). 

Smoking and Thrombosis/Fibrinolysis 

In a pathology study of plaque tissue obtained 

from samples of diseased arteries removed by surgery, 

plaques from smokers were more frequently complicated by thrombosis along the walls of the arteries than 

were plaques from nonsmokers (Spagnoli et al. 1994). 

Proper balance of the tightly regulated coagulationfibrinolytic systems is critical to plaque stability and 

blood flow in the later phases of atherosclerosis. This 

balance between clotting and dissolution of clots depends on extremely complex interactions involving all 

of the cellular components in the blood-arterial wall 

interface, especially the endothelial cells and platelets. 

When this complex system is disturbed, pathologic 

thrombosis may occur, leading to vascular occlusion 

by thrombus fragments that could result in clinically 

manifest infarcts. The association between cigarette 

smoking and changes in blood vessels that are conducive to thromboses has been previously described 

(USDHHS 1990; Miller et al. 1998). Evidence suggests 

that these prothrombotic effects of smoking may be 

most important to the natural history of atherosclerosis, and probably are the main underlying factors associating smoking with sudden cardiac death (Burke 

et al. 1997). 

The prothrombotic effects associated with cigarette smoking stem partially from the effects of smoking on the endothelium, as discussed in the preceding 

section. Endothelial denudation exposes circulating 

plasma coagulation factors to the prothrombotic matrix of arterial and plaque tissue. Moreover, impaired 

endothelial function results in disturbances of the 

tightly regulated physiologic interface between blood 

components and vessel walls, leading, for example, to 

homeostatic disruptions and increased levels of plasma 

vWF (Blann et al. 1998). Recent experimental evidence 

in smoke-exposed animals concurs with parallel comparisons of human carotid artery specimens from 

smokers and nonsmokers (Matetzky et al. 2000), indicating that smoking increases tissue factor expression 

(a small molecular-weight glycoprotein that initiates 

the extrinsic clotting cascade [Toschi et al. 1997]). 

Together, these animal and human findings suggest 

yet another mechanism whereby smoking may increase the risk for acute arterial thrombosis (Matetzky 

et al. 2000). 

Furthermore, the direct effects of smoking on the 

properties of platelets, platelet activation, and platelet 

adhesion are well proven (Lassila et al. 1988; Lakier 

1992), and even nonsmokers exposed to cigarette 

smoke experience acute increases in platelet aggregability (Davis et al. 1985). As in the endothelial damage 

discussed above, neither aspirin nor rutosides 

prevented these acute effects on platelet activity (Davis 

et al. 1986). Smoking also elevates the plasma concentration of beta-thromboglobulin and the platelet 

factor, thereby increasing the tendency toward clot formation (Davis et al. 1986).

 More recent experiments reinforce and further 

clarify these earlier results. In controlled experiments 

using habitual smokers with stable CHD (Hung et al. 

1995), blood obtained five minutes after smoking two 

cigarettes had increases in platelet thrombus formation and whole blood platelet aggregation compared 

with blood obtained five minutes before smoking. In 

another experiment, the increased aggregability of 

platelets in smokers was related to increases in fibrinogen and platelet-fibrinogen binding (Fusegawa et al. 

1999). 

With regard to fibrinolytic activity, studies have 

shown that compared with the endothelium of nonsmokers, the endothelium of smokers has a reduced 

ability to release TPA in response to an infusion of substance P, an endothelium-dependent vasodilator 

(Newby et al. 1999, 2001). This impaired TPA response 

may be critical in the acute phase of coronary thrombosis by slowing the conversion of fibrin into soluble 

products. In combination with the prothrombotic effects of smoking, the imbalance in the coagulationfibrinolytic systems may precipitate the propagation 

of microthrombi in the surface of atheromatous 

plaques, leading to arterial occlusion and clinical manifestations of thrombosis (Newby et al. 1999). Evidence 

also strongly suggests that smoking has synergistic 

effects with some pharmacologic substances (e.g., oral 

contraceptives) in its thrombogenic potential 

(Lidegaard 1999; Roy 1999). 

Fibrinogen is an acute-phase protein that rises 

quickly in response to a number of stimuli (Gabay and 

Kushner 1999), and in cross-sectional studies, smoking is strongly associated with increased plasma levels of fibrinogen (Ernst et al. 1987; Folsom et al. 1991, 

1992; Miller et al. 1998). In addition, prospective cohort studies show that persons who start or continue 

to smoke have larger increases in plasma fibrinogen 

Cardiovascular Diseases 367 
Surgeon General’s Report 

over time than do nonsmokers (Meade et al. 1987; 

Folsom et al. 2000), findings supported by a short-term 

experiment showing decreases in plasma fibrinogen 

following smoking cessation (Rothwell et al. 1991). 

Thus, the smoking-associated increase in plasma levels may reflect a chronic inflammatory response associated with the insult to the arterial tissue and other 

organs (e.g., bronchitis) from long-term smoking. Numerous studies have demonstrated that the fibrinogen level is an independent cardiovascular risk factor 

(Wilhelmsen et al. 1984; Kannel et al. 1987; Ernst and 

Resch 1993; Danesh et al. 1998), and the deleterious 

effects of smoking on CVD risk may be partially mediated by the rise in fibrinogen. 

The profound alterations of the fibrinolytic system associated with smoking are also reflected in the 

strong association between cigarette smoking and 

plasma levels of certain hemostatic factors. Smoking 

is associated with increased antithrombin III activity 

(Folsom et al. 1992) and decreased levels of protein C 

(Conlan et al. 1993b), factor VIII (Conlan et al. 1993a), 

factor IX activation peptide, factor X activation peptide, and prothrombin fragment 1+2 (Miller et al. 1998). 

In contrast to the increases in vWF levels experimentally induced by cigarette smoking (Blann et al. 1998), 

cross-sectional studies do not show a significant independent association between cigarette smoking status 

and average vWF plasma levels (Conlan et al. 1993a). 

The results for factor VIIc are not consistent in the literature, with significant associations in some studies 

(Miller et al. 1998) but not in others (Folsom et al. 1992). 

Smoking and Inflammation 

Current concepts of the pathogenesis of atherosclerosis increasingly emphasize the central role of inflammation (Ross 1999). As discussed elsewhere in this 

report, smoking induces a localized inflammatory response in the lungs and induces a systemic inflammatory response manifested by elevations in 

inflammatory markers such as the leukocyte count in 

circulating blood, which is a risk marker (and potentially a risk factor) of CVD (Friedman et al. 1973). Both 

cross-sectional and longitudinal studies have consistently demonstrated that, compared with persons with 

lower counts, those with moderately elevated leukocyte counts have an increased risk of CHD, stroke, and 

sudden death (Friedman et al. 1974, 1975; Prentice et 

al. 1982; Grimm et al. 1985; Ernst et al. 1987). In a recent meta-analysis, a difference of 2,800 leukocytes/ 

mm3

 within the normal range of the leukocyte count 

(e.g., comparing persons with 8,400 leukocytes/ 

mm3 with persons with 5,600 leukocytes/mm3) was 

associated with a relative risk (RR) of CHD of 1.4 

(Danesh et al. 1998). 

The association between cigarette smoking and 

the leukocyte count is strong and well described in 

epidemiologic studies (Friedman et al. 1973). There are 

consistent dose-response relationships with amount 

smoked, degree of inhalation, duration of smoking, 

and amount of time since quitting (Petitti and Kipp 

1986; Nieto et al. 1992) (see Chapter 2, “Cancer”). Moreover, studies demonstrate that these acute increases in 

leukocyte counts caused by cigarette smoking are probably due, at least in part, to local inflammatory effects 

in the bronchial tree (Lehr 1993). However, the effects 

of cigarette smoking on the activation and adhesion 

of leukocytes, which initiate the atherosclerotic process when combined with endothelial dysfunction, are 

perhaps more significant for arterial wall injury. Laboratory studies have demonstrated that both animal and 

human leukocytes exposed to cigarette smoke express 

increased chemotactic responses, increased aggregability, and increased expressions of adhesion receptors in response to a variety of stimuli (Anderson 1991; 

Lehr 1993). 

Smoking is also associated with an elevation of 

the C-reactive protein level, an acute phase protein that 

provides a measure of inflammatory activity (Das 1985; 

Tracy et al. 1997; Ridker et al. 2000). Epidemiologic 

evidence indicates that the C-reactive protein level is 

positively associated with risks of CHD, stroke, and 

peripheral arterial disease (Kuller et al. 1996; Ridker 

et al. 1997; Ridker 2001; Di Napoli et al. 2001). 

Smoking, Lipids, and Lipid Metabolism 

The evidence supporting an association between 

smoking and adverse lipid profiles has been reviewed 

in previous reports (USDHHS 1990), and summarized 

in a 1989 meta-analysis of 54 studies (Craig et al. 1989). 

This evidence reveals higher concentrations of total 

LDL and very low-density lipoprotein (VLDL) cholesterol in smokers compared with nonsmokers, although 

the most consistent evidence indicates decreased levels of high-density lipoprotein (HDL) cholesterol in 

smokers compared with nonsmokers (Krupski 1991). 

The plausibility of a causal association of smoking 

with decreased HDL is supported by evidence from a 

population-based, prospective cohort study within the 

Stanford Five-City Project showing decreasing HDL 

levels in persons starting to smoke and, conversely, 

increasing HDL levels in persons who had stopped 

smoking (Fortmann et al. 1986). These findings have 

been replicated in other studies (USDHHS 1990). 

368 Chapter 3 
The Health Consequences of Smoking 

Smoking may also seriously affect lipid metabolism and LDL modification. Smokers have higher levels of serum malondialdehyde (USDHHS 1990), which 

may modify LDL cholesterol to promote uptake by 

macrophages and decrease cholesterol transport from 

cell membranes to plasma. Malondialdehyde may be 

a marker of oxidation, and evidence indicates that 

smoking may promote lipid peroxidation, which is 

hypothesized to be one key element in the causal pathway of atherogenesis (Steinberg et al. 1989). Furthermore, evidence from an uncontrolled intervention trial 

demonstrates a significant increase in the HDL/LDL 

cholesterol ratio in adult smokers without disease 

following an eight-week period of smoking reduction. 

The increase was even more pronounced after a further eight-week period of abstinence from smoking 

(Eliasson et al. 2001). How cigarette smoking could 

cause changes in serum lipid levels is not entirely understood, but the mechanisms may involve metabolic 

changes affecting the transport of cholesterol between 

cells and plasma (de Parscau and Fielding 1986). In 

laboratory studies, cigarette smoke stimulated the 

generation of oxidized LDL cholesterol in human 

plasma (Frei et al. 1991). 

Smokers also have elevated levels of plasma and 

urine F2

-isoprostanes (by-products of lipid peroxidation) compared with nonsmokers (Morrow et al. 1995; 

Patrono and FitzGerald 1997). Even though no acute 

effects of smoking were observed, experimental data 

demonstrated that stopping smoking resulted in a significant reduction in F2

-isoprostane levels within days 

or just a few weeks. This finding suggests that the in 

vivo oxidation injury associated with cigarette smoking almost completely disappears within a few weeks 

of smoking cessation (Morrow et al. 1995; Oguogho et 

al. 2000). 

Smoking and Cardiovascular Function 

In addition to the atherogenic effects of smoking, components of cigarette smoke may have adverse 

effects on the cardiovascular system with regard to 

oxygen supply and demand, thereby increasing the 

risk of ischemia. These effects may ultimately precipitate clinical events in persons with compromised 

coronary circulation that stems from underlying 

atherosclerosis. 

Smoking and Increased Oxygen Demand 

Cigarette smoking induces the release of catecholamines (epinephrine and norepinephrine) (Cryer 

et al. 1976; Hung et al. 1995), which are associated with 

an increased baseline heart rate and contractility and 

an increase in vascular tone (Benowitz 1988). In smokers, however, cigarette smoking is associated with a 

lower than expected heart rate in response to physical 

exercise (Srivastava et al. 2000), a characteristic that 

has been associated with increased risks of mortality, 

arrhythmias, and MI (Lauer et al. 1999). 

Even though there is no evidence that smoking 

is associated with chronic hypertension, there is compelling evidence that smoking acutely increases 

peripheral vascular resistance and increases blood 

pressure (Cryer et al. 1976; Koch et al. 1980). These 

effects seem to be attributable to the pharmacologic 

properties of nicotine (Benowitz and Gourlay 1997). 

In carefully controlled experiments in healthy humans, 

cigarette smoking increased blood pressure and the 

sympathetic nervous system stimulation to both the 

blood vessels and the heart (Narkiewicz et al. 1998). 

Acute and episodic increases in blood pressure, 

coupled with an increased heart rate, increase the 

oxygen demands of the myocardium. However, in 

population studies, cigarette smokers tend to have on 

average lower blood pressures than do nonsmokers 

(USDHEW 1979; Friedman et al. 1982). 

Smoking, Decreased Oxygen Supply, 

and Increased Blood Rheology 

Studies have long indicated that smoking is associated with a decrease in coronary blood flow (Martin et al. 1984). More recent studies using intracoronary 

Doppler measurements have demonstrated that smoking causes an immediate constriction of both proximal and distal coronary arteries as well as an increase 

in coronary vessel tone and hence resistance (Quillen 

et al. 1993). These effects seem to be mediated by increases in catecholamine levels associated with smoking, suggested by the finding that pharmacologically 

blocking alpha-adrenergic receptors can reverse the 

smoking-induced decrease in coronary blood flow in 

CHD patients (Winniford et al. 1986; Quillen et al. 

1993). The decreased vasodilatory response to certain 

stimuli resulting from the endothelial dysfunction associated with smoking also can limit blood perfusion 

to the myocardial tissue in certain situations. 

The effects of smoking in compromising the oxygen supply to tissues, particularly to the myocardium, 

are not limited to vasomotor effects but also can be 

due to smoking-related changes in key physiologic 

blood components. Carbon monoxide in cigarette 

smoke diffuses from the pulmonary alveoli to the 

bloodstream, binds to hemoglobin in the erythrocyte, and forms carboxyhemoglobin, which has a 

Cardiovascular Diseases 369 
Surgeon General’s Report 

diminished oxygen-carrying capacity. Compensatory 

erythrocytosis may result (Rampling 1993). Both hematocrit and hemoconcentration increase with the 

number of cigarettes smoked. These increases, combined with the hyperfibrinogenemia associated with 

smoking (see the section on “Smoking and Thrombosis/Fibrinolysis” earlier in this chapter), contribute to 

the increased blood viscosity associated with smoking, which increases the risk of thrombosis and physically compromises microcirculation (Rampling 1993). 

The low-grade inflammatory response associated 

with smoking not only results in increased plasma fibrinogen levels, but also seems to be responsible for 

the consistently demonstrated dose-response association between smoking and leukocyte counts (see the 

section on “Smoking and Inflammation” earlier in this 

chapter). The level of C-reactive protein, a marker for 

chronic inflammation and a strong predictor of clinical CHD events (Ridker and Haughie 1998), was associated with pack-years of smoking among persons 

more than 65 years old in the Cardiovascular Health 

Study (CHS) cohort (Tracy et al. 1997). This association was present even among persons who had 

stopped smoking for 30 years or more, suggesting that 

some of the deleterious effects of smoking on inflammation may persist. These data are consistent with the 

hypothesis that smoking causes a chronic, increased 

inflammatory response, especially in the absence of 

other mitigating factors (Tracy et al. 1997). 

The net result of all of these mechanisms (reduced 

oxygen-carrying capacity of hemoglobin and compromised microcirculation from increased blood viscosity and leukocytosis) is a reduction in the oxygendelivery capacity of blood both to the heart and to the 

peripheral tissues. When oxygen demand is increased, 

the resulting tissue hypoxemia may create a critical 

imbalance of oxygen need with supply in a person with 

underlying coronary or peripheral atherosclerosis. 

Smoking is associated with significant myocardial 

perfusion abnormalities (Deanfield et al. 1986), thus 

explaining the increased risk for MI events, unstable 

angina, and sudden deaths observed in smokers with 

CHD (Quillen et al. 1993). 

Despite abundant laboratory and epidemiologic 

data linking smoking and a variety of pathophysiologic 

mechanisms in arterial wall and blood interactions, 

specific components of smoking responsible for each 

of these effects are not entirely clear (Pittilo 1990). Both 

nicotine and carbon monoxide may be involved in 

inducing endothelial dysfunction and atherosclerosis, 

although the evidence (animal experiments and laboratory studies of tissue cultures) is not consistent 

in singling out a specific component as uniquely 

responsible (Pittilo 1990). Some studies show that nicotine administration to animals results in endothelial 

abnormalities—increases in the number of endothelial cell carcasses in the blood and decreases in the 

synthesis of prostacyclin (an inhibitor of platelet 

aggregation) by endothelial cells (Pittilo 1990). In addition, nicotine seems to be responsible for the platelet activation induced by smoking (Lassila et al. 1988). 

However, a recent study compared a number of hematologic and coagulation indices in smokers before 

quitting, after quitting but using nicotine gum or 

patches, and subsequently when no longer using any 

nicotine products (Blann et al. 1997). There were significant declines in most outcomes measured after 

smoking cessation but few changes after stopping the 

nicotine gum and/or patches. A similar pattern was 

found in a study of atherogenic and thrombogenic factors in persons attending a smoking cessation program 

who received either a nicotine nasal spray or a placebo (Ludviksdottir et al. 1999). 

Epidemiologic studies have addressed the potential role of nicotine by investigating the risks of heart 

disease from different forms of tobacco use. Cigar 

smoking has been associated with an elevated risk for 

heart disease, but cigar smokers have high intakes of 

both nicotine and carbon monoxide (Goldman 1977; 

Pechacek et al. 1985; Iribarren et al. 1999). Of greater 

interest is the risk for heart disease associated with the 

use of smokeless oral tobacco, which delivers nicotine 

rapidly into the bloodstream (Fant et al. 1999). Because 

of prolonged absorption of nicotine through the buccal mucosa, smokeless tobacco delivers a larger overall exposure to nicotine than cigarette smoking does 

(Gritz et al. 1981). Smokeless tobacco users are reportedly at an increased risk for high blood pressure 

(Bolinder et al. 1992) but not for elevated levels of fibrinogen (Eliasson et al. 1995). 

One study of Swedish men followed approximately 6,000 smokeless tobacco users for 12 years and 

compared their cause-specific mortality with that of 

tobacco smokers and nonsmokers. Although the RR 

for all CVD was lower than that for tobacco smokers 

(1.8 [95 percent confidence interval (CI), 1.6–2.0] for 

smokers of <15 cigarettes per day and 1.9 [95 percent 

CI, 1.7–2.2] for smokers of 15 cigarettes per day), 

smokeless tobacco users had a statistically increased 

RR for all CVD of 1.4 (95 percent CI, 1.2–1.6) compared 

with those who used no tobacco products (Bolinder et 

al. 1994). The RRs were high for those aged 35 through 

54 years at entry into the study. Adjusting for age, body 

mass index (BMI), blood pressure, diabetes, and a history of heart symptoms or blood pressure medication 

at the time of entry did not alter the results. In 

370 Chapter 3 
The Health Consequences of Smoking 

contrast, two case-control studies from Sweden have 

not found that smokeless tobacco is a risk factor for 

MI (Huhtasaari et al. 1992, 1999). However, in one of 

these studies (Huhtasaari et al. 1999), restricting the 

analysis to fatal cases of MI (including sudden death) 

showed a tendency toward an increased risk for snuff 

dippers. 

Carbon monoxide also compromises the oxygencarrying and oxygen-delivering capacity of the blood, 

thus promoting the complications of atherosclerosis. 

Free radicals present in cigarette smoke may also be 

involved in atherogenesis by promoting oxidative 

changes in LDL (Church and Pryor 1985). Oxidized 

LDL is more readily taken up by macrophages to form 

foam cells in the atherosclerotic plaque and can be directly involved in promoting endothelial and vasomotor dysfunction (Kaufmann et al. 2000). Furthermore, 

toxic and reactive glycation products found in aqueous extracts of tobacco can modify certain lipoproteins 

(Apo B), prevent the normal tissue uptake of LDL, and 

increase levels of circulating LDL (Zieske et al. 1999). 

These effects explain the epidemiologic findings of 

higher concentrations of total, LDL, and VLDL cholesterol in smokers than in nonsmokers (Craig et al. 

1989). 

Summary 

A substantial body of laboratory and experimental evidence now demonstrates that cigarette smoking in general and some specific components of 

cigarette smoke affect a number of basic pathophysiologic processes at the critical interface between circulating blood components and the inner arterial wall. 

Smoking leads to endothelial injury and cell dysfunction. The effects of cigarette smoking on circulation produce a substantial shift in the hemostatic balance at 

the endothelium, leading to atherosclerosis and its 

thrombotic complications. Furthermore, components 

of cigarette smoke diminish the ability of the blood to 

carry oxygen and increase the physiologic demands 

of the myocardium. The overall result of this constellation of toxic effects is to profoundly and adversely 

affect the homeostatic balance in the cardiovascular 

system, thus explaining the well-documented relationship between smoking and both subclinical and clinical manifestations of atherosclerosis that are reviewed 

in the next sections. 

Smoking and Subclinical Atherosclerosis
 

Epidemiologic Evidence 

Atherosclerosis is the most common cause of 

obstruction within the blood vessels supplying the 

lower extremities. When the obstruction reduces the 

blood flow sufficiently, a variety of symptoms may occur. The symptoms usually originate in areas distal to 

the obstruction, but flow from the collateral vessels 

can alter the pattern. The most common symptom is 

intermittent claudication, which can cause persons to 

feel pain in their legs when exercising, but the pain 

typically resolves within several minutes after the exercise has stopped. The pain is usually localized to the 

calf, because the most commonly affected vessels are 

the superficial femoral and popliteal arteries. Epidemiologic studies indicate that about 5 percent of men 

and 2.5 percent of women over 60 years of age experience intermittent claudication (Jelnes et al. 1986). 

Noninvasive studies of the peripheral arteries find a 

prevalence of peripheral arterial disease at least three 

times higher than the self-reported prevalence of intermittent claudication. One poor outcome of peripheral arterial disease is leg amputation. In 1995, the 

above- and below-knee amputation rate for legs was 

25 per 100,000 adult Americans (Feinglass et al. 1999). 

Studies investigating clinical cardiovascular 

events among adults middle-aged or older are limited 

in that they only address the factors related to the late 

phases of the natural history of atherosclerosis. It is 

widely recognized that this disease has a long natural 

history, with early pathologic changes (fatty streaks) 

developing in the teens or early twenties in many persons (Strong and McGill 1969; Strong et al. 1999). Thus, 

research addressing only associations between risk factors and clinical events that are late outcomes may 

overlook or underestimate the effects of risk factors in 

the early stages of atherogenesis and may miss possible opportunities for prevention. Moreover, inferences from studies of clinical events can be limited 

because of changes in behavior resulting from 

Cardiovascular Diseases 371 
Surgeon General’s Report 

symptoms, which in turn could distort the temporal 

relationship (reverse causality) between suspected risk 

factors and outcomes. The distortion of this temporal 

relationship can be particularly problematic in crosssectional data, as symptoms or disease diagnosis may 

influence smokers to quit or to reduce the number of 

cigarettes smoked. Such changes in smoking are documented in a study that compared cross-sectional and 

longitudinal associations between cigarette smoking 

and other risk factors with both clinical and subclinical CVD (Nieto et al. 1999). 

Studying subclinical markers for atherosclerosis 

offers an informative complement to disease outcomes 

for examining the association between risk factors and 

earlier phases of atherosclerosis (Table 3.2). Subclinical outcomes are less susceptible to temporal biases, 

and their use makes it possible to study the pathogenesis of the disease at an earlier stage. When researchers study healthy persons in an epidemiologic setting, 

measures of subclinical disease need to be noninvasive, 

imposing no risk and minimizing the burden on study 

participants (Sharrett 1993). 

Table 3.3 describes results of studies reported 

since 1990 that examined the association between cigarette smoking and the presence of atherosclerosis, using carotid intimal-medial thickness (IMT) as the 

marker for subclinical disease because of its strong 

association with incident CHD (Chambless et al. 1997) 

and with stroke events (Chambless et al. 2000). Conducted with adult populations from different countries, these studies showed a remarkably consistent 

positive association between smoking and carotid IMT. 

Furthermore, studies that examined trends of IMT with 

the amount smoked found evidence of a dose-response 

relationship. Smoking also was associated with 

changes in carotid IMT in three prospective cohort 

studies (Salonen and Salonen 1990; Belcaro et al. 1995; 

Howard et al. 1998a). In a study of participants in the 

Atherosclerosis Risk in Communities (ARIC) Study 

who were free of CVD at baseline, cigarette smoking 

was a strong risk factor for both the presence of greater 

baseline carotid IMT and the incidence of CHD events 

during the three-year follow-up period (Sharrett et al. 

1999). Results from pooled analyses using ARIC Study 

and CHS data indicated that smoking seemed to be 

strongly related to carotid atherosclerosis, regardless 

of age. These data show a stronger association in older 

than in middle-aged white adults in the studies 

(Howard et al. 1997). 

The association between clinical manifestations 

of peripheral arterial disease and smoking is well established (USDHEW 1979; USDHHS 1990; Krupski 

1991). Furthermore, recent studies have added new 

insights into the critical role of smoking in the natural 

history, severity, and progression of peripheral arterial disease. In a six-year follow-up study of patients 

with intermittent claudication, current smokers had a 

higher incidence of severe ischemic leg symptoms 

ranging from rest pain to gangrene (Smith et al. 1998). 

More subtle changes also have been documented in 

prospective studies. Among 415 peripheral arterial 

disease patients with intermittent claudication (aged 

42 through 88 years), smoking was strongly related to 

a six-minute walk performance (Cahan et al. 1999). 

Patients with intermittent claudication who were current smokers (but had been asked to refrain from smoking on the day of the experiment) had significantly 

decreased time to claudication and more severe pain 

than patients who had quit smoking an average of 

seven years earlier (Gardner 1996). In this study the 

effect of smoking remained significant even after controlling for baseline ankle-arm index (AAI), also known 

as ankle-branchial index, an index of the degree of underlying peripheral arterial disease (Janzon et al. 1981). 

Experimental data also demonstrate acute effects of 

smoking on the peripheral circulation among persons 

with peripheral arterial disease. In a cross-over study 

of chronic smokers with peripheral arterial disease, 

Table 3.2 Markers of subclinical atherosclerosis used in epidemiologic studies 

Disease 

Generalized atherosclerosis 

Marker 

Ankle-arm index 

Carotid intimal-medial thickness 

Study technique 

Blood pressure measured with Doppler 

B-mode ultrasound 

Coronary atherosclerosis Coronary calcium Computerized tomography 

Cerebrovascular disease Lacunar infarcts Magnetic resonance imaging 

372 Chapter 3 
The Health Consequences of Smoking 

smoking two cigarettes significantly decreased the AAI 

compared with the AAI on comparison days when the 

participants refrained from smoking (Yataco and 

Gardner 1999). These recent experiments, including 

findings from studies using an objective measure of 

the underlying peripheral arterial disease (the AAI), 

call into question earlier claims that smoking did not 

have an effect on exercise performance in this population (Waller et al. 1989). 

Table 3.4 summarizes results from studies on 

smoking and the AAI. The AAI is the systolic blood 

pressure of the ankle divided by the systolic blood 

pressure of the arm, and was proposed as an index of 

subclinical peripheral arterial disease in the early 1980s 

(Janzon et al. 1981), with lower values indicating disease. It is a consistently strong predictor not only of 

peripheral arterial disease outcomes but also of coronary and cerebrovascular disease events among adults 

middle-aged (Zheng et al. 1997) and older (Criqui et 

al. 1992; Newman et al. 1999). Most of the results in 

Table 3.4 also show a consistent association between 

cigarette smoking and the AAI in diverse study populations and in both older and younger adults. These 

results are also consistent with the association between 

smoking and clinical peripheral arterial disease 

(USDHHS 1989, 1990). 

The presence of subclinical CVD can be assessed 

by the presence of cerebral white matter disease or lacunar infarcts in magnetic resonance imaging (MRI) 

of the brain in asymptomatic persons. Results from 

studies reporting on the association between smoking 

status and MRI findings are not consistent for either 

abnormality, as shown in Table 3.5. Whereas some 

studies showed an increased prevalence of white matter disease and brain infarcts in smokers compared 

with nonsmokers (Longstreth et al. 1996, 1998; Liao et 

al. 1997; Howard et al. 1998b), other studies did not 

show statistically significant differences (Breteler et al. 

1994; Yamashita et al. 1996; Shintani et al. 1998). The 

studies with the largest samples did find positive 

trends, but only a few reached conventional levels of 

statistical significance. 

All of the studies of white matter disease are 

cross-sectional, however, and thus subject to methodologic limitations (e.g., prevalence-incidence bias). For 

example, even if smoking is truly associated with an 

increased risk (incidence) of the underlying disease 

(e.g., subclinical atherosclerosis) and if smoking also 

affects disease prognosis, the prevalence ratio obtained 

in a cross-sectional study will be a biased estimate of 

the RR. If smoking increases the risk of clinical events 

and mortality in those with atherosclerosis (e.g., by 

promoting thrombosis [see the section on “Smoking 

and Thrombosis/Fibrinolysis” earlier in this chapter]), 

survival of smokers with atherosclerosis will be shorter 

than that of nonsmokers, and thus the prevalence ratio will underestimate the RR. Because this limitation 

may have different effects in different settings and 

populations, it is a possible explanation for some of 

the inconsistent results across different studies. 

A combined index of subclinical atherosclerosis 

in participants aged 65 years or older in the CHS was 

constructed using the electrocardiogram, echocardiogram, carotid IMT, AAI, and responses to a questionnaire that asked about symptoms of angina and 

intermittent claudication (Kuller et al. 1994). Current 

smokers in this study, excluding persons with a clinical disease, were more than twice as likely to have 

evidence of a subclinical disease in multivariate analyses that adjusted for other major risk factors. The ageadjusted proportions of current smokers without evidence of CVD were 8 percent in men and 6 percent in 

women; 16 percent and 14 percent, respectively, had 

evidence of subclinical disease; and 13 percent and 9 

percent, respectively, manifested a clinical disease 

(these numbers reflect the fact that persons with a clinical disease tend to quit smoking). In the CHS, after 

excluding those with evidence of clinical CVD, the adjusted odds ratios (ORs) for a subclinical disease comparing smokers with nonsmokers were 2.0 (95 percent 

CI, 1.5–2.7) in women and 2.4 (95 percent CI, 1.6–3.6) 

in men (Kuller et al. 1994). 

All of the evidence discussed so far in this section pertains to studies of smoking and subclinical 

atherosclerosis in vascular beds other than coronary 

arteries. Until recently, direct assessment of subclinical coronary atherosclerosis in epidemiologic studies 

was not feasible because there were no noninvasive 

measurements suitable for studies in asymptomatic 

persons. And although studies using coronary angiography have documented an association between smoking and the presence and degree of coronary artery 

narrowing (Pearson 1984; Chen et al. 1995), inferences 

from these studies are limited because of the possibility of selection biases stemming from characteristics 

of the study participants; even the comparison group 

(those without angiographic evidence of disease) had 

some clinical indications on the diagnostic angiography (Pearson 1984). 

Evidence from pathology studies on a series of 

autopsies of adults regardless of the cause of death 

demonstrated clear and strong associations between 

smoking histories and the presence of aortic and 

coronary atherosclerosis (Strong and Richards 1976). 

These early findings have been strengthened by additional pathology studies of young trauma victims 

Cardiovascular Diseases 373 
Surgeon General’s Report 

Table 3.3	 Studies on the association between smoking and atherosclerosis using the carotid B-mode 

ultrasound findings 

Study	 Design/population Age/gender 

Salonen and Salonen 1990 Community-based 

Cohort 

Finland 

n = 100 

42–60 years 

Men 

Bonithon-Kopp et al. 1991 Community-based 

Cross-sectional 

France 

n = 517 

45–54 years 

Women 

Heiss et al. 1991 ARIC† Study 

Community-based 

Case-control 

United States 

n = 386 case-control pairs 

45–54 years 

Both genders 

Salonen and Salonen 1991 Population-based 

Cohort 

Finland 

n = 1,224 

42, 48, 54, or 60 years 

Men 

Bots et al. 1992 Rotterdam Elderly Study 

Community-based 

Cross-sectional 

Netherlands 

n = 954 

55 years 

Both genders 

O’Leary et al. 1992 Cardiovascular Health Study 

Community-based 

Cross-sectional 

United States 

n = 5,201 

65 years 

Both genders 

Fine-Edelstein et al. 1994 Framingham Heart Study 

Community-based 

Cross-sectional 

United States 

n = 1,116 

66–93 years 

Both genders 

*IMT = Intimal-medial thickness. 

†

ARIC = Atherosclerosis Risk in Communities. 

‡

OR = Odds ratio.
 §

CI = Confidence interval.
 

Cigarette-years = The number of years of smoking multiplied by the number of cigarettes smoked per day.
 ¶Maximum common carotid artery wall thickness.
 

**Maximum internal carotid artery wall thickness.
 

374 Chapter 3 
The Health Consequences of Smoking 

Main results Comments 

Progression of IMT* over 2 years: 

Smokers 0.21 mm increase 

Nonsmokers 0.09 mm increase 

Differences remained significant after 

adjusting for age, lipids, leukocyte count, 

and platelet aggregability 

Percentage with Percentage with 

carotid thickening plaque 

Smokers 35 10 

Nonsmokers 28 8 

The association was significant after adjusting 

for age, blood pressure, and lipids 

Multivariate-adjusted OR‡ of carotid atherosclerosis 

(high IMT) (95% CI§) 

Ever vs. never smokers 3.1 (2.1–4.6) 

Current vs. never smokers 3.9 (2.9–5.9) 

Cases and controls were matched for age, 

gender, race, and center, with additional 

adjustments for all other major risk factors 

Cigarette-years were strongly associated with the 

maximal IMT ( = 0.125, p <0.0001) 

Adjusted for age, ambulatory blood pressure, 

serum low-density lipoprotein cholesterol, 

history of ischemic heart disease, pre-exercise 

systolic blood pressure, and diabetes 

Percentage of internal Percentage of 

carotid artery stenosis current smokers 

0 23 

1–15 26 

16 32 

The increasing percentage of current smoking 

with higher levels of stenosis remained statistically significant after adjusting for main risk 

factors 

Smoking status 

Carotid IMT (mm) Never Former Current

Maximum common¶ 0.98 1.03 1.03

 Maximum internal** 1.39 1.59 1.71

 Maximum stenosis (%) 16 20 24 

All differences were statistically significant 

even after adjusting for all main risk factors 

Multivariate-adjusted OR for carotid stenosis 

comparing current with never smokers 

Men 2.81 (p = 0.002) 

Women 3.07 (p = 0.0001) 

There was a statistically significant linear 

dose-response relationship with the amount 

smoked 

Cardiovascular Diseases 375 
Surgeon General’s Report 

Table 3.3 Continued 

Study Design/population Age/gender 

Howard et al. 1994 ARIC† Study 

Community-based 

Cross-sectional 

United States 

n = 12,953 

45–64 years 

Both genders 

Salonen et al. 1994 Cohort (from Seven Countries Study) 

Finland 

n = 182 

70–89 years 

Men 

Belcaro et al. 1995 Community-based sample 

Cohort 

Italy 

n = 472 

40–60 years 

Both genders 

Diez-Roux et al. 1995 ARIC Study (Washington County) 

Community-based 

Historical cohort 

United States 

n = 2,073 

45–64 years 

Both genders 

Bonithon-Kopp et al. 1996 European Vascular Aging Study 

Community-based 

Cross-sectional 

France 

n = 1,384 

59–71 years 

Both genders 

Wei et al. 1996 Community-based 

Cohort 

San Antonio, Texas (United States), and 

Mexico City, Mexico 

n = 867 

35–64 years 

Both genders 

Howard et al. 1998a ARIC Study 

Community-based 

Cohort 

United States 

n = 10,914 

45–64 years 

Both genders 

*IMT = Intimal-medial thickness. 

†

ARIC = Atherosclerosis Risk in Communities. 

††ETS = Environmental tobacco smoke. 

‡‡Pack-years = The number of years of smoking multiplied by the number of packs of cigarettes smoked per day. 

376 Chapter 3 
The Health Consequences of Smoking 

Main results Comments 

Mean IMT* (mm) 

Never smokers

No ETS†† exposure 0.693

With ETS exposure 0.705 

Former smokers 0.756 

Current smokers 0.761 

Among former and current smokers, more 

pack-years‡‡ of exposure were associated 

with an increased IMT 

In 1989 relative risk for current smoking = 2.46 

(95% CI, 0.94–6.45) with nonmineralized atheroma 

and 1.21 (95% CI, 0.22–6.58) with any mineralization; 

former smoking = 1.99 (95% CI, 0.99–4.00) with 

nonmineralized atheroma and 1.15 (95% CI, 0.37–3.62) 

with any mineralization 

Adjusted for age (continuous), cholesterol 

(mmol/L), and pulse pressure (mm Hg) 

The progression of carotid atherosclerosis (change 

in IMT) was slightly higher in smokers than in 

nonsmokers, but differences were not statistically 

significant 

Only controlled for age 

Carotid IMT was associated with both current smoking and smoking status 15 years before the ultrasound 

measurement 

ETS exposure, either concurrent with or 15 

years before the ultrasound measurement, 

was also associated with carotid IMT 

Current smokers (%) 

Common carotid IMT tertile No plaque Plaque

 Lower (<0.58 mm) 6.4 12.5

 Medium (0.58–0.68 mm) 8.7 15.0

 Higher (>0.68 mm) 11.1 11.4 

Differences were statistically significant 

Among current smokers, = 0.0028 mm (p = 0.84) for 

IMT for common carotid arteries, and = 0.0508 mm 

(p = 0.02) for internal carotid arteries 

Adjusted for age, gender, city, diabetes, 

total and high-density lipoprotein 

cholesterol, systolic blood pressure, 

and triglycerides 

Adjusted IMT 

progression (μm/3 years) 

Never smokers

No ETS exposure 25.9

 With ETS exposure 31.6 

Former smokers

 No ETS exposure 32.8

 With ETS exposure 38.8 

Current smokers 43.0 

The association between smoking and IMT 

was strongest among persons with diabetes 

and persons with hypertension 

Cardiovascular Diseases 377 
Surgeon General’s Report 

Table 3.3 Continued 

Study Design/population Age/gender 

Davis et al. 1999 Community-based 

Cohort 

United States 

n = 182 men and 136 women 

33–42 years 

Both genders 

Espeland et al. 1999 Case-control 

Population-based 

United States 

n = 280 (141 cases with 50% stenosis of 

1 vessel, 139 controls with no lumen 

irregularities) 

45 years 

Both genders 

*IMT = Intimal-medial thickness. 

documenting an increased prevalence of advanced lesions and a decreased prevalence of intermediate lesions in young smokers compared with nonsmokers. 

Data from the Bogalusa Heart Study (Berenson et al. 

1998) and from the Pathobiological Determinants of 

Atherosclerosis in Youth (PDAY) Study (Strong et al. 

1999) show that cigarette smoking by young people 

remains associated with atherosclerosis. Both studies 

involved careful assessments of the extent of atherosclerotic lesions found in young victims of trauma. 

Berenson and colleagues (1998) described the association between atherosclerosis and smoking among 93 

participants in the Bogalusa Heart Study who had died 

and were autopsied. Antemortem risk factor information was available from study records; most died from 

trauma at a mean age of 21 years. Smoking was associated with fibrous plaques in the aorta and fatty 

streaks in the coronary vessels even at this young age. 

The PDAY Study is a multicenter autopsy study 

of atherosclerosis in trauma victims aged 15 through 

34 years. Even among the youngest persons in the 

study, atherosclerotic lesions were found in the aortas 

of nearly all persons and in the coronary arteries of 

the majority (Strong et al. 1999). The extent of atherosclerosis increased with age. Several analyses of the 

PDAY specimen data have shown that active smoking 

was associated with the extent of atherosclerosis 

(PDAY Research Group 1990; Zieske et al. 1999; McGill 

et al. 2001). McGill and colleagues (2001) reported on 

the findings in 629 men and 227 women, and they 

found that smoking was associated with atherosclerosis in the aortas but not in the coronary arteries. Zieske 

and colleagues (1999) carefully examined coronary 

arteries from 50 smokers and 50 nonsmokers in the 

study. They found that smokers were twice as likely 

to have advanced lesions as nonsmokers, suggesting 

that lesions progress more rapidly in smokers. 

New imaging techniques are now being used to 

noninvasively assess markers of early coronary artery 

disease. With recent technological advances, it is now 

possible to conduct epidemiologic studies of the presence of coronary calcium as a surrogate for the presence of atherosclerosis in coronary arteries of healthy 

asymptomatic persons. The presence of calcium in 

plaques is an indicator of atherosclerosis. Using computed tomography (CT) techniques (i.e., helical CT or 

electron-beam CT [EBCT]), researchers can directly 

study subclinical atherosclerosis in coronary arteries. 

Studies measuring coronary calcium in epidemiologic 

settings (i.e., in population-based samples of asymptomatic persons) are in progress, but only a few studies with selected samples have been published. In two 

studies with samples that included adults selected 

because of the presence of cardiovascular risk factors 

but not necessarily a history of a clinical event (Goel 

et al. 1992; Wong et al. 1994), a history of smoking was 

significantly associated with the presence of coronary 

calcium in multivariate analyses. 

In contrast to these results, studies of clinical 

populations (i.e., patients with acute coronary syndromes) show an inverse association between smoking and the presence of coronary calcium measured 

by EBCT (Schmermund et al. 1998). Furthermore, another study from an employee screening program of 

French men (Simon et al. 1995) found no association 

between current smoking and coronary calcium 

378 Chapter 3 
The Health Consequences of Smoking 

Main results Comments 

Pack-years of smoking were significant risk factors 

for carotid IMT* in men ( = 0.0018, standard 

error = 0.0009 [p <0.05]) 

Adjusted for age, systolic blood pressure, and 

low-density lipoprotein cholesterol 

For all participants, smoking (μm/pack-years) 

was associated with a 2.25 mm ± 0.49 (p <0.0001) 

IMT increase, and for cases only a 1.91 mm + 1.04 

(p <0.0001) increase for all sites measured 

Adjusted for age, blood pressure, glucose, 

lipids, and body mass index; IMT sites included common segments, bifurcation segments, internal segments, near walls, and 

far walls 

measured with ultrafast CT. In this same group the 

degree of extracoronary plaque found in carotid, aortic, and femoral arteries based on ultrasound measurements was strongly associated with smoking. The 

authors interpreted the contrast between the results 

for coronary calcium and extracoronary plaque in 

this study as a reflection of the fact that coronary calcification represents a more advanced lesion than 

uncalcified plaque, and may be influenced by the cumulative, long-term effects of smoking rather than by 

a current exposure to tobacco smoke (Simon et al. 1995). 

Evidence Synthesis 

Recently developed techniques can measure 

markers of subclinical atherosclerosis in healthy persons in community settings. These techniques have 

now been applied in a number of cohort and crosssectional studies with repeated findings of a higher 

frequency of abnormalities in smokers. Consistently, 

both cross-sectional and cohort studies measuring carotid artery wall thickness or the AAI have demonstrated strong, dose-response associations between 

smoking and the presence and progression of subclinical atherosclerosis. Results from earlier autopsy studies and the PDAY and Bogalusa studies also suggest 

that smoking affects the progression of intermediate 

to advanced atherosclerotic lesions at early ages. 

Knowledge of the underlying mechanisms by which 

smoking causes atherosclerosis adds plausibility to 

these observations. Smoking has immediate adverse 

effects on the homeostatic balance of the cardiovascular system. 

Studies using other markers, such as the presence of silent brain infarcts or white matter disease 

detected by an MRI or coronary calcium measured 

with CT, have been less consistent in their findings, 

possibly because of the limitations imposed by their 

cross-sectional nature. Longitudinal studies in progress 

will provide further data for examining the association between smoking and the development and progression of these subclinical markers. 

Conclusion 

1.	 The evidence is sufficient to infer a causal relationship between smoking and subclinical 

atherosclerosis. 

Implications 

Cigarette smoking has a causal relationship with 

the full natural history of atherosclerosis from the time 

that it can be detected by sensitive, subclinical markers to its late and often fatal stages. The new findings 

on subclinical disease indicate the potential for preventing more advanced and clinically symptomatic 

disease through quitting smoking and maintained 

cessation. 

Cardiovascular Diseases 379 
Surgeon General’s Report 

Table 3.4	 Studies on the association between smoking and clinical peripheral arterial disease using the 

ankle-arm index (AAI) 

Study	 Design/population Age/gender 

Newman et al. 1993 Cardiovascular Health Study 

Community-based 

Cross-sectional 

United States 

n = 5,201 

65 years 

Both genders 

Kornitzer et al. 1995 Occupational cohort 

Cross-sectional 

Belgium 

n = 2,023 

40–55 years 

Men 

Curb et al. 1996 Honolulu Heart Program 

Retrospective cohort 

United States 

n = 3,450 

71–93 years 

Both genders 

Hooi et al. 1998 Limburg Peripheral Arterial Occlusive 

Disease (PAOD) Study 

Community-based 

Cross-sectional 

Netherlands 

n = 3,650 

40–78 years 

Both genders 

Shinozaki et al. 1998 Occupational cohort 

Cross-sectional 

Japan 

n = 446 

43 years (mean)Δ 

Men 

Fabsitz et al. 1999 Strong Heart Study 

Community-based 

American Indians 

Cross-sectional 

United States 

n = 4,549 

45–74 years 

Both genders 

*OR = Odds ratio. 

†

CI = Confidence interval. 

‡

ABI = Ankle/brachial blood pressure index.
 §

Pack-years = The number of years of smoking multiplied by the number of packs of cigarettes smoked per day.
 

No age range was provided.
 

380 Chapter 3 
The Health Consequences of Smoking 

Main results Comments 

Adjusted OR* for the AAI <1.0 associated with 

smoking was 2.55 

All differences were statistically significant 

even after adjusting for all main risk factors 

(history of diabetes, increasing age, nonwhite 

race) 

AAI 0.90 was significantly associated with smoking In multivariate analyses, the association with 

smoking was not significant (p = 0.09) 

Adjusted OR (95% CI†) for the ABI‡ <0.9 measured in 

1991–1993 was associated with current smoking: 

Cross-sectionally (smoking in 1991–1993): 4.32 

(2.92–6.39) 

Longitudinally (smoking in 1965–1968): 2.82 

(2.15–3.69) 

Pack-years§ were also associated with AAI in a 

dose-response fashion 

Among persons without intermittent claudication, 

ABI <0.95 was significantly associated with smoking 

status 

Smoking was more strongly associated with 

symptomatic than with asymptomatic PAOD 

Adjusted OR for AAI <1.0 associated with smoking 

was 1.74 (95% CI, 1.31–2.99) 

None 

A low AAI (<0.9) was significantly associated with 

current cigarette smoking and with pack-years 

Associations persisted in multivariate analyses 

with age, systolic blood pressure, current 

cigarette smoking, pack-years of smoking, 

albuminuria (micro and macro), low-density 

lipoprotein cholesterol level, and fibrinogin 

level 

Cardiovascular Diseases 381 
Surgeon General’s Report 

Table 3.5	 Studies on the association between smoking and the presence of subclinical cardiovascular 

disease using brain magnetic resonance imaging 

Study Design/population Age/gender 

Breteler et al. 1994 Rotterdam Elderly Study 

Community-based 

Cross-sectional 

Netherlands 

n = 111 

65–84 years 

Both genders 

Longstreth et al. 1996 CHS† 

Community-based 

Cross-sectional 

United States 

n = 3,301 

65 years 

Both genders 

Yamashita et al. 1996 Cross-sectional 

Japan 

n = 246 

50–75 years 

Men 

Liao et al. 1997 ARIC§ Study 

Cross-sectional 

Community-based 

United States 

n = 1,920 

51–70 years 

Both genders 

Howard et al. 1998b ARIC Study 

Community-based 

Cross-sectional 

United States 

n = 1,737 

55–72 years 

Both genders 

Longstreth et al. 1998 CHS 

Community-based 

Cross-sectional 

United States 

n = 3,660 

65 years 

Both genders 

*WML = White matter lesion. 

†

CHS = Cardiovascular Health Study. 

‡

Pack-years = The number of years of smoking multiplied by the number of packs of cigarettes smoked per day.
 §

ARIC = Atherosclerosis risk in communities.
 

HDL = High-density lipoprotein.
 ¶BMI = Body mass index.
 

382 Chapter 3 
The Health Consequences of Smoking 

Main results Comments 

No association was observed between the presence 

of WMLs* and current or former smoking after 

adjusting for age and gender 

No substantial change in the results was found 

after further adjustments for a previous stroke 

and myocardial infarction 

In analyses adjusted for age and gender, ever smoking cigarettes (p <0.001) and more pack-years‡

 of 

smoking (p <0.05) were associated with WML grade 

None 

Cigarette smoking was not related to silent brain 

infarctions 

No adjustments were mentioned 

Age, race, and gender were adjusted proportionally 

by WML grade 

WML grade 

Normal Mild Moderate Severe

 0 1 2 3–9 

Smoking status

 Current smokers 12.3 45.0 24.5 18.2

 Former smokers 13.4 52.5 22.9 11.3

 Never smoked 16.5 49.8 22.7 10.9 

Linear trend was statistically significant 

(p = 0.004) 

Odds ratios (OR) for silent cerebral infarctions: 

OR OR when adjusted 

for other risk factors 

Smoking status

 Nonsmokers 1 1

 Smokers exposed to 1.03 1.06

 environmental tobacco

 smoke

 Former smokers 1.32 1.16

 Current smokers 2.13 1.88 

Cigarette smoking had a significant ordinal 

association (p = 0.029); other risk factors 

included demographics, cerebrovascular 

disease risk factors (HDL , triglycerides, 

hypertension, and diabetes), and lifestyle 

factors (fat and alcohol intake, BMI¶, and 

physical activity) 

In analyses adjusted for age and gender, pack-years 

were associated with silent lacunar infarcts (p <0.05) 

None 

Cardiovascular Diseases 383 
Surgeon General’s Report 

Table 3.5 Continued 

Study Design/population Age/gender 

Shintani et al. 1998 Hospital-based 

Cross-sectional 

Japan 

n = 270 

40–87 years 

Both genders 

Smoking, Coronary Heart Disease, and Sudden Death
 

Epidemiologic Evidence 

Coronary Heart Disease 

CHD results from atherosclerosis of the coronary 

arteries. Atherosclerosis is evident in persons as young 

as 20 years of age but becomes more severe with clinically evident manifestations in middle to older adulthood. The category of CHD includes MI, ischemic heart 

disease, and angina pectoris. MI results from an interruption of blood flow through the coronary arteries to 

the myocardium, with acute injury and then scarring 

and permanent damage to the heart muscles. Ninety 

percent of those who die from sudden cardiac death 

have at least two coronary arteries with about 90 percent occlusion. Angina pectoris refers to the chest pain 

a person experiences resulting from a lack of blood 

flow to the heart muscle. 

The United States has experienced an epidemic 

of CHD for the past 50 years, and CHD remains the 

leading cause of death for Americans. In 2003, an estimated 1.1 million Americans had a new or recurrent 

coronary attack (AHA 2002). In spite of treatment advances, the prognosis after a coronary event is still 

poor, as 25 percent of men and 38 percent of women 

die within one year after a recognized MI. Due to primary and secondary prevention interventions and 

better quality of care for CHD, age-specific death rates 

from CHD have been substantially declining during 

the last four decades (Gillum 1994). However, compared with a decline of approximately 25 percent in 

rates between 1978 and 1997 in the United States, the 

actual number of deaths has only declined by approximately 9 percent over the same period because the 

American population is aging. Although 85 percent of 

those who die of CHD are 65 years or older, CHD also 

affects younger adults. In Americans younger than 65 

years of age, approximately 80 percent of CHD mortality occurs during the first coronary event (AHA 

2002). 

Previous Surgeon General’s reports have reviewed the evidence firmly establishing that smoking 

is a major cause of CHD (USDHHS 1990). Since these 

reports, there have been several additions to the large 

body of evidence previously considered. First, the new 

data support a causal association between smoking 

and MI across various racial and ethnic groups 

(USDHHS 1998). Second, smoking has been identified 

as a strong risk factor for MI in women younger than 

50 years of age (Rosenberg et al. 1985; Croft and 

Hannaford 1989), even though the incidence of MI is 

very low in this population. A case-control study of 

women younger than 44 years of age (mean age 41 

years) found that the OR for MI showed a strong doseresponse relationship, with a risk of 2.47 (95 percent 

CI, 1.12–5.45) for those smoking 1 to 5 cigarettes per 

day and rising to 74.6 (95 percent CI, 33–169) for those 

smoking more than 40 cigarettes per day compared 

with nonsmokers (Dunn et al. 1999). The reported 

population attributable risk for tobacco use and MI in 

this group was 73 percent. Third, in data on female 

384 Chapter 3 
The Health Consequences of Smoking 

Main results Comments 

There was no association between silent lacunar 

infarctions and smoking habits with or without 

adjusting for other main risk factors (serum levels 

or total cholesterol, HDL cholesterol, triglycerides, 

lipoprotein(a), hemoglobin A1c, age, gender, systolic 

blood pressure, diastolic blood pressure, duration of 

hypertension, family history, alcohol intake, obesity 

[BMI], and atrial fibrillation) 

None 

smokers from the study by Prescott and colleagues 

(1998), the highest risk (6.8) for MI was in women 

younger than 55 years of age. Fourth, prospective cohort results based on approximately 1,100 coronary 

disease events observed in a 14-year follow-up of about 

86,000 women from the Nurses Health Study (Stampfer 

et al. 2000) showed strong dose-response relationships 

between the number of cigarettes smoked per day and 

the risk of CHD. The adjusted RRs of CHD for former 

smokers, for women smoking 1 to 14 cigarettes per day, 

and for those smoking 15 or more cigarettes per day 

were 1.55, 3.12, and 5.48, respectively, compared with 

lifetime nonsmokers. A further analysis of the Nurses 

Health Study suggests that the reduction in smoking 

observed in this cohort from 1980–1994 explains about 

13 percent of the concurrent decline in CHD incidence 

(Hu et al. 2000). Finally, whereas most of the earlier 

evidence has come from studies in populations of predominantly European origin, recent studies have also 

demonstrated that the association between smoking 

and CHD is of a similar magnitude in other ethnic 

groups, such as African Americans (Liao et al. 1999; 

Rosenberg et al. 1999). 

A recent meta-analysis summarized the cohort 

studies that measured the effect of smoking cessation 

on mortality after having an MI (Wilson et al. 2000). 

Thirteen studies meeting the analysis criteria were 

reviewed. The combined OR in former smokers compared with current smokers, based on a random effects model for death after MI, was 0.54 (95 percent 

CI, 0.46–0.62), with no significant heterogeneity among 

the studies. There was no difference in the OR for studies published before and after 1980. The results did 

not vary by gender, age, country in which the study 

took place, or the quality of the study. 

The beneficial impact of smoking cessation on 

survival after acute MI is well established. Several recent studies show that cessation is beneficial at the time 

of and after percutaneous coronary artery vascularization for CHD. At the time of revascularization, substantial differences between risk factor profiles in 

smokers and nonsmokers have been observed. About 

one-third of those who receive percutaneous coronary 

artery vascularization are current smokers, and 50 to 

60 percent continue to smoke after the procedure. Probably because of the thrombogenic properties of tobacco 

smoking, smokers are usually younger, have had angina for a shorter period of time, and have more favorable profiles for other traditional cardiac risk factors, such as hypertension and hypercholesterolemia, 

than their nonsmoking counterparts. This more favorable risk factor profile may explain the better outcomes 

for smokers found in several studies (Barbash et al. 

1995). 

For studies of outcomes after percutaneous coronary artery vascularization, careful consideration 

needs to be given as to which measure to use. Because 

cigarette smoking may increase the rate of restenosis, 

using repeat percutaneous coronary artery vascularization procedures or coronary artery bypass surgery 

as the outcome is problematic. However, many physicians are reluctant to recommend invasive procedures 

for patients who continue to smoke, even if their symptoms return (Underwood and Bailey 1993). One of the 

largest studies with a broad assessment of outcomes 

is based on 5,437 patients who had a successful percutaneous coronary artery revascularization and were 

followed for a mean of 4.5 years (Hasdai et al. 1997). 

Persistent smokers were at significantly greater risks 

for electrocardiographically confirmed infarctions 

Cardiovascular Diseases 385 
Surgeon General’s Report 

and death than were nonsmokers, and this trend was 

evident when compared with those who quit smoking after the vascularization. Persistent smokers were 

less likely to have a repeated percutaneous procedure 

or coronary bypass surgery than were nonsmokers, but 

this difference could be due to a reluctance by clinicians to recommend invasive procedures for those who 

are still at a higher risk for atherogenesis as a consequence of smoking (Hasdai et al. 1997). 

Dose-response relationships between tobacco 

smoking and CVD have been readily established for 

the highest levels of cigarette smoking, but most studies have not had a sufficient sample size to assess the 

level of risk for those smoking only a few cigarettes 

per day. A recent report assessed 25-year mortality 

rates for the 12,763 men in the Seven Countries Study. 

Compared with nonsmokers, those smoking one to 

nine cigarettes per day had a hazard ratio of 1.2 (95 

percent CI, 0.99–1.44) for CHD, 1.3 (95 percent CI, 0.51– 

3.28) for other arterial diseases (Jacobs et al. 1999), and 

1.3 (95 percent CI, 1.17–1.43) for total deaths. All of 

these results were adjusted for baseline cohort of residence, age, BMI, serum cholesterol, systolic blood pressure, and the presence of clinical CVD. 

During the past 40 years, there have been numerous changes in cigarette design and manufacturing, 

with sharp declines in tar and nicotine yields according to measurements based on the Federal Trade Commission protocol (National Cancer Institute [NCI] 

1996). During this same interval, a number of casecontrol studies have assessed cigarette type or tar and 

nicotine yields and the risk for CVD including MI, 

CHD mortality, and stroke. The possibility that loweryield products might be associated with lower risks 

for CHD draws plausibility from the postulated roles 

of both nicotine and carbon monoxide in increasing 

the risks for MI. 

However, studies conducted since the 1960s have 

not consistently found lower risks for CHD in smokers of lower-yield cigarettes (Table 3.6). For acute MI, 

large case-control studies show that risk does not vary 

with measures of tar, nicotine, or carbon monoxide 

yields. Several cohort studies do show lower mortality rates from CHD among users of lower-yield products, but the effects are small. The American Cancer 

Society Cancer Prevention Study I (CPS-I) found that 

smokers of lower-tar cigarettes had slightly lower 

mortality rates from heart disease compared with 

smokers of high-tar cigarettes (Hammond et al. 1976). 

In contrast, neither a case-control study of men 

(Kaufman et al. 1983) nor that of women (Palmer et al. 

1989) found any association between cigarette tar 

yields and the risk of nonfatal MI, and a case-control 

study from Italy conducted in the late 1980s also failed 

to identify a clear trend between cigarette tar yields 

and risks of acute MI (Negri et al. 1993). 

Several more recent studies have found that lowtar cigarettes appear to slightly lower the risks of CHD 

associated with tobacco smoking (Tang et al. 1995). 

Four cohorts of British men (n = 56,255) first enrolled 

in 1967 and followed for an average of 13 years were 

assessed for all-cause and CHD mortality. An estimated 18 percent of the cohort who smoked manufactured cigarettes reported smoking primarily plain (unfiltered) cigarettes. The RR for CHD (0.76 [95 percent 

CI, 0.56–1.03]) was lower among filter-tipped cigarette 

smokers compared with smokers of plain cigarettes. 

Point estimates for mortality from each smokingrelated disease were consistently lower for filter-tipped 

cigarette smokers than for plain cigarette smokers, 

but only the relative mortality for all smoking-related 

diseases was significantly different (RR = 0.83 [95 percent CI, 0.68–1.00]). Another major study investigating the impact of low-tar cigarettes on CHD was based 

on 13,926 cases and 32,389 controls in the United Kingdom sample of the International Studies of Infarct Survival clinical trial (Parish et al. 1995). Tar yield was 

classified based on self-reports of the brand of cigarettes usually smoked. For this cohort, almost all 

smoked filter-tipped cigarettes, and 25 percent used 

low-tar brands. Because a reduction in tar yields had 

already occurred by the time of the study, no participants were classified in the high-tar category. With 

standardization for age, gender, and the daily number 

of cigarettes smoked, the incidence of MI was 10.4 percent higher in medium-tar compared with low-tar cigarette smokers (p = 0.06). Among persons aged 30 

through 59 years, the incidence was 16.6 percent higher 

(p = 0.02). 

There has been a continued suggestion that the 

association of smoking with CVD risk and with CHD 

risk specifically could reflect an inadequate control of 

confounding by lifestyle-related risk factors. Countering this argument are the findings of many studies 

showing that carefully controlling for these other risk 

factors does not substantially change the strength of 

the smoking-CVD association. A recent analysis from 

the Cancer Prevention Study II (CPS-II) of more than 

900,000 adults examined the changes in relative and 

attributable risks for CHD associated with smoking, 

comparing models that only adjusted for age with 

models that also adjusted for other risk factors (Thun 

et al. 2000). The risk estimates for CHD outcomes were 

unchanged with multivariate adjustments for potential confounders in both men and women and younger 

and older persons. The total number of annual CHD 

386 Chapter 3 
The Health Consequences of Smoking 

deaths in the United States attributable to smoking 

changed from an estimated 91,500 in the age-adjusted 

only model to an estimated 94,200 in the multivariate 

model that controlled for aspirin use, alcohol consumption, BMI, physical activity, and dietary fat consumption. Thus, controlling for major risk factors had little 

consequence, and it is doubtful that there would be 

substantial residual confounding by other factors, 

whether known or still unknown. In fact, it seems unlikely that there are still unknown risk factors that have 

both sufficiently strong associations with cigarette 

smoking and sufficiently strong effects on CHD risk 

to be important confounders of the smoking-CHD association. 

Sudden Death 

Sudden death is the sudden, abrupt loss of heart 

function in a person who may or may not have a diagnosed heart disease, for whom the time and mode of 

death are unexpected, and for whom death occurs instantly or shortly after the onset of symptoms (AHA 

2002). Sudden cardiac death is usually due to cardiac 

arrest from untreated cardiac arrhythmias, and it may 

have been the first manifestation of CHD. 

Cigarette smoking might increase the risk of sudden cardiac death by increasing platelet adhesiveness, 

releasing catecholamines, causing acute thrombosis, 

and promoting ventricular ectopy (arrhythmias). The 

morphology of cardiac vessels is different in smokers 

than in nonsmokers who die suddenly from coronary 

disease. Smokers are more likely to have acute thrombosis than stable plaques at the time of death, but the 

frequency of plaque rupture and eroded plaque that 

cause thrombosis is the same in smokers and nonsmokers (Burke et al. 1997). Evidence also indicates 

that nicotine affects the conductance of myocardial cell 

channels, providing a plausible mechanism for the 

putative association of cigarette smoking (and smokeless tobacco use) with arrhythmias and sudden death 

(Wang et al. 2000). 

Cigarette smoking has been associated with sudden cardiac death of all types. During 26 years of 

follow-up in the Framingham Heart Study, there were 

177 sudden deaths in men and 50 in women. One-half 

of the deaths in men and 75 percent of those in women 

occurred without evidence of prior CHD. Smokers had 

a RR of 2.5 compared with nonsmokers (p <0.001), and 

men had a higher RR for smoking than women (Kannel 

et al. 1975). In the Nurses Health Study, women who 

smoked more than 25 cigarettes per day died of CHD 

at a much higher rate than nonsmokers (RR = 5.4 

[95 percent CI, 3.0–10.4]), but the risk was similar for 

nonfatal MI (RR = 5.8 [95 percent CI, 4.2–8.0]) (Willett 

et al. 1987). A case-control study of Tasmanian men 

found a threefold increase in the risk of sudden, unexpected cardiac death from current smoking (Sexton et 

al. 1997). In a study based on the National Mortality 

Followback Survey, current smoking was associated 

with an adjusted OR of 1.8 (95 percent CI, 1.2–2.7) for 

sudden death in those without a history of CHD 

(Escobedo and Caspersen 1997). Although many studies document the relationship between tobacco smoking and sudden cardiac death, the association does not 

seem to be stronger than the relationship between 

tobacco smoking and MI or CHD in general. 

Nicotine has well-characterized effects on the 

cardiovascular system and increases heart rate through 

activiation of the sympathetic nervous system 

(USDHHS 1988). Smoking is associated with increased 

risk for sudden cardiac death in men and women 

(USDHHS 1983; Albert et al. 2003). This association 

might reflect underlying artherosclerosis caused by 

smoking and possibly an effect of nicotine itself. 

Congestive Heart Failure 

Smoking-caused CHD may contribute to CHF. 

In contrast to CHD and stroke, the incidence of CHF 

is increasing. An estimated 4.6 million Americans have 

CHF, and 43,000 persons die from CHF every year. In 

the third National Health and Nutrition Examination 

Survey (NHANES), the prevalence of CHF ranged 

from 6.2 percent for men between 55 and 64 years of 

age to 9.8 percent for men over 75 years of age. The 

corresponding figures are 3.4 percent and 9.7 percent, 

respectively, for women (AHA 2002). 

Since tobacco smoking has been causally linked 

to MI and CHD, it is reasonable to consider the extent 

to which smoking may contribute to causing CHF. 

Within six years of a recognized MI, 22 percent of men 

and 46 percent of women will be disabled with heart 

failure (Ho et al. 1993). Survival after the onset of CHF 

is poor. According to Framingham Study data collected 

between 1948 and 1988, five-year survival rates are 25 

percent for men and 38 percent for women with CHF 

(Ho et al. 1993). In the first NHANES Epidemiologic 

Follow-up Study, cigarette smoking was an independent risk factor (RR = 1.59 [95 percent CI, 1.39–1.83]) 

for the development of CHF over the 19-year followup (He et al. 2001). The estimated population 

attributable risk for tobacco smoking was 17.1 percent, 

higher than any other risk factor with the exception of 

pre-existing CHD. This estimate may be low because 

the contribution of tobacco smoking to pre-existing 

CHD was not included in this estimate. Since CHD is 

Cardiovascular Diseases 387 
Surgeon General’s Report 

Table 3.6	 Studies on the association between smoking low-yield cigarettes and the risk of cardiovascular 

disease (CVD) 

Study Design/population Variable analyzed 

Hammond et al. 1976 Cohort study of 1 million volunteers 

in the American Cancer Society Cancer 

Prevention Study followed from 

1960–1972 

Tar content (high: 25.8– 

35.7 mg/cigarette, 

medium: 17.6–25.7 mg/ 

cigarette, low: <17.6 

mg/cigarette) 

Hawthorne and Fry 1978 Prospective follow-up study of 18,786 

persons attending a multiphasic screening 

examination from 1965–1977; Scotland 

Filter-tipped vs. plain 

cigarettes 

Todd et al. 1978 Prospective cohort study of 10,063 

persons aged 35–69 years in a 12.4 year 

follow-up period from 1965–1977, from 

a random sample in Great Britain 

Filter-tipped vs. plain 

cigarettes 

Lee and Garfinkel 1981 Prospective mortality study of >1 

million men and women in a 12-year 

follow-up period from 1960–1972; 

United States 

Tar yield: low/high 

Higenbottam et al. 1982 Cohort study of 17,475 male civil 

servants aged 40–64 years, and a 

sample of 8,089 male British residents 

aged 35–69 years 

Current cigarette 

smoking habits 

Borland et al. 1983 Prospective cohort of the Whitehall Study 

of 4,910 men who smoked cigarettes with 

known carbon monoxide (CO) yields, 

followed from 1976–1979; Great Britain 

CO yields 

Kaufman et al. 1983 Case-control study of 1,337 men aged 

30–54 years; northeastern United States 

Nicotine and CO yields 

*CHD = Coronary heart disease. 

†

RR = Relative risk. 

‡

CI = Confidence interval. 

§

MI = Myocardial infarction. 

388 Chapter 3 
The Health Consequences of Smoking 

Outcome Results 

CHD* mortality Compared with high-tar smokers: CHD standardized mortality ratio = 

1.03 for medium-tar smokers and 0.82 for low-tar smokers 

CVD mortality RR† of CVD mortality = 1.05 for smokers of filter-tipped cigarettes 

compared with smokers of plain cigarettes 

CHD mortality RR for men = 0.75 for smokers of filter-tipped cigarettes compared with 

smokers of plain cigarettes; and 1.03 for women who smoked filtertipped cigarettes compared with women who smoked plain cigarettes 

CHD mortality RR for men = 0.90 for smokers of low-tar yield cigarettes compared 

with smokers of high-tar yield cigarettes; and 0.81 for women smokers 

of low-tar yield cigarettes compared with women smokers of high-tar 

yield cigarettes 

CHD mortality Ten-year CHD mortality rates per 100 deaths standardized for age; 

employment grade among inhalers = 4.29 for consuming 1–9 

cigarettes/day, 5.98 for 10–19 cigarettes/day, 6.56 for 20 cigarettes/ 

day; among noninhalers, 3.48 for 1–9 cigarettes/day, 5.73 for 10–19 

cigarettes/day, and 5.18 for 20 cigarettes/day; coronary deaths were 

more common among inhalers; effects of tar/nicotine yields were 

confined to inhalers 

CHD mortality RR = 1.47 in those smoking cigarettes with <18 mg CO yield compared 

with smokers of cigarettes with 20 mg CO yield, adjusted for age, 

grade of employment, cigarettes/day, and tar yield; persons smoking 

high CO-yield cigarettes (>20 mg) smoked fewer cigarettes/day 

MI§ RR = 2.8 (95% CI‡

, 2.0–4.0) for current smokers compared with 

nonsmokers; risk varied with number of cigarettes smoked (up to 7.5 

[95% CI, 3.7–15.3] for men aged 30–44 years who smoked 45 cigarettes/ 

day); little or no significance was found comparing lower with higher 

nicotine yields: 3.0 (95% CI, 1.9–4.9) for <0.8 mg/cigarette to 2.6 (95% CI, 

1.5–4.4) for 1.5 mg/cigarette; or in CO levels: 2.7 (95% CI, 1.5–4.8) for 

<10 mg/cigarette to 2.8 (95% CI, 1.5–5.1) for 19 mg/cigarette 

Cardiovascular Diseases 389 
Surgeon General’s Report 

Table 3.6 Continued 

Study Design/population Variable analyzed 

Alderson et al. 1985 Case-control study of 12,693 in-patients 

from 1977–1982; Great Britain 

Always filter-tipped vs. 

plain cigarettes 

Petitti and Friedman 

1985 

Prospective cohort study of 16,270 current 

regular cigarette smokers and 42,113 persons 

who never used any form of tobacco, from 

1979–1983; United States 

Low-yield cigarette use 

Palmer et al. 1989 Case-control study of 910 women <65 

years of age with incident MI, and 2,375 

hospital controls; United States 

Low-yield cigarette use 

Kuller et al. 1991 Prospective cohort study of a 10-year 

follow-up of the Multiple Risk Factor 

Intervention Trial of men from 

1972–1985; United States 

Tar and nicotine levels 

Negri et al. 1993 Multicenter case-control study, 916 

patients with acute MI without a history 

of IHD¶ and 1,106 controls admitted to 

the hospital for acute conditions unrelated to risk factors for IHD, between 

September 1988 and June 1989, from over 

80 coronary care units in various regions 

of Italy 

Cigarette tar and 

nicotine yields 

Parish et al. 1995 Hospital-based, case-control study of 

4,923 recently discharged MI cases and 

6,880 controls, all current smokers of 

cigarettes with known tar yields, early 

1990s, United Kingdom 

Tar yields of manufactured cigarettes were 

assessed at the beginning of the study 

OR = Odds ratio. 

§

IHD = Ischemic heart disease. 

390 Chapter 3 
The Health Consequences of Smoking 

Outcome Results 

CHD mortality Aged 35–54 years: OR = 1.78 for men who always smoked filtertipped cigarettes compared with men who always smoked plain 

cigarettes; 0.24 for women who always smoked filter-tipped cigarettes 

compared with women who always smoked plain cigarettes; aged 

55–74 years: OR = 2.67 for men who always smoked filter-tipped 

cigarettes compared with men who always smoked plain cigarettes; 

1.32 for women who always smoked filter-tipped cigarettes compared 

with women who always smoked plain cigarettes; all ORs were 

adjusted for the number of cigarettes/day 

CVD and MI§ RR = 1.15 (95% CI, 1.05–1.27) for CVD per 5.0 mg increase in tar among 

current cigarette smokers compared with nonsmokers, adjusted for 

age, gender, and race; RR = 1.22 (95% CI, 1.00–1.50) for acute MI per 5.0 

mg increase in tar among current cigarette smokers compared with 

nonsmokers, adjusted for age, gender, and race; CVD risk was consistently higher in smokers of higher-yield cigarettes compared with 

smokers of lower-yield cigarettes (small differences in magnitude) 

Nonfatal MI risk RR = 4.7 (95% CI, 2.8–8.0) for current smokers who smoked brands 

with the lowest nicotine levels (<0.40 mg/cigarette) compared with 

lifetime nonsmokers; 4.2 (95% CI, 2.4–7.2) for smokers of higher-yield 

brands (>1.30 mg) 

CHD mortality Compared with men who smoked cigarettes with nicotine levels 1 mg, 

RR = 1.04 (95% CI, 0.8–1.35) for men who smoked cigarettes with 1.1–1.4 

mg and 1.27 (95% CI, 0.92–1.77) for men who smoked cigarettes with 

1.5 mg; compared with men who smoked cigarettes with tar levels 

15 mg, RR = 1.08 (95% CI, 0.8–1.45) for men who smoked cigarettes with 

16–19 mg and 1.19 (95% CI, 0.86–1.65) for men who smoked cigarettes 

with 20 mg; estimates were adjusted for age, serum cholesterol, diastolic 

blood pressure, and cigarettes/day; low-tar and low-nicotine cigarette 

smokers smoked more cigarettes/day 

MI risk Compared with nonsmokers, RR = 3.8, 4.3, 3.2, and 3.7 for the four 

categories of tar yield (<10, 10–15, 16–20, and >20 mg/cigarette, 

respectively); there was no trend in risk across yields when the analysis 

was restricted to smokers; RR = 1.2, 0.8, and 1.0 for higher-yield 

categories, respectively, compared with the lowest-yield category; 

RR = 9.3–12.6 for persons aged <50 years but no trend was observed 

with increasing yields; thus, lower-tar yields were not effective for 

reducing MI morbidity 

Incident nonfatal MI After standardization for age, gender, and amount smoked, the rate 

was 10.4% higher (standard deviation = 5.4) in medium-tar ( 10 mg/ 

cigarette) than in low-tar (<10 mg/cigarette) cigarette smokers 

(p = 0.06) 

Cardiovascular Diseases 391 
Surgeon General’s Report 

Table 3.6 Continued 

Study Design/population Variable analyzed 

Tang et al. 1995 Four cohort studies of 56,255 men 

between 1967 and 1982 from the British 

United Provident Association Study 

(London), Whitehall Study (London), 

Paisley-Renfrew Study (Scotland), 

and United Kingdom Heart Disease 

Prevention Project 

Tar yields of manufactured plain and filtertipped cigarettes were 

assessed at the beginning of the study 

Powell et al. 1997 Case-control study, 291 smokers with 

newly referred peripheral arterial 

disease, 828 controls without the 

disease, from outpatient clinics, 1988– 

1992, London, United Kingdom 

Tar and nicotine yields 

and carboxyhemoglobin 

levels 

the underlying cause for roughly 65 percent of CHF 

cases, the risk of CHF from smoking is probably mediated through CHD. 

Evidence Synthesis 

These new data reaffirm the already welldocumented causal association of smoking with the 

risk for CHD. Compared with lifetime nonsmokers, 

the RR in smokers rises with the number of cigarettes 

smoked and falls after cessation. The type of cigarette 

smoked has little influence on CHD risk. The association cannot be explained by confounding. 

Conclusions 

1.	 The evidence is sufficient to infer a causal relationship between smoking and coronary heart disease. 

2.	 The evidence suggests only a weak relationship 

between the type of cigarette smoked and coronary heart disease risk. 

Implications 

Because of its prevalence, smoking is a major 

cause of CHD, particularly among younger smokers. 

While CHD mortality rates have continued to fall, a 

substantial proportion of the population’s burden of 

CHD could be avoided with smoking prevention and 

cessation. Products with lower yields of tar and 

nictotine, as measured by a smoking machine, have 

not been found to reduce CHD risk substantially and 

they are not a lower-risk alternative for smokers who 

cannot quit. By causing CHD and MI, smoking may 

also contribute to the development of CHF, an increasingly frequent disease that is disabling and has a poor 

prognosis. 

392 Chapter 3 
The Health Consequences of Smoking 

Outcome Results 

Mortality from CHD and stroke Compared with lifetime nonsmokers, RR for CHD = 1.21 (95% CI, 

1.06–1.38) for former smokers, 2.05 (95% CI, 1.73–2.42) for current 

smokers of plain cigarettes, and 1.94 (95% CI, 1.70–2.21) for current 

smokers of filter-tipped cigarettes; RR for stroke = 1.0 (95% CI, 0.73– 

1.36) for former smokers, 1.98 (95% CI, 1.36–2.88) for current smokers 

of plain cigarettes, and 1.62 (95% CI, 1.19–2.21) for current smokers of 

filter-tipped cigarettes; risk of IHD and stroke showed an interaction 

with age; relative mortality in cigarette smokers of a 15 mg decrease in 

tar yield/cigarette was 0.77 (95% CI, 0.61–0.97) for CHD and 0.86 (95% 

CI, 0.50–1.50) for stroke 

Peripheral arterial disease OR = 1.75 for smokers of cigarettes with 14 mg tar compared with 

smokers of cigarettes with <9 mg; 1.54 for smokers of cigarettes with 

1.2 mg nicotine compared with smokers of cigarettes with <0.8 mg; 

1.62 for whole blood carboxyhemoglobin 4.5% among cases compared 

with whole blood carboxyhemoglobin <2.7% among controls; all ORs 

were adjusted for age, gender, and depth of inhalation 

Smoking and Cerebrovascular Disease
 

Cerebrovascular disease is a syndrome of neurologic deficits resulting from interruptions in the arterial blood flow to the brain. Deficits range from mild 

to severe, depending on the zone of the brain that is 

affected, and can be transitory (transient ischemic attack) or permanent (stroke). In the United States, the 

incidence of stroke is an estimated 600,000 cases per 

year. The one-year, case-fatality rate is about 30 percent, and strokes caused an estimated 160,000 deaths 

in the United States in 1996 (the third leading cause of 

death after CHD and malignant neoplasms). According to estimates from the AHA (2002), there are approximately 4.6 million stroke survivors in the United 

States, with cases equally distributed between women 

and men. 

The causes of strokes are either ischemic (brain 

infarction stemming from a reduction of blood flow 

because of local atherothrombosis or emboli from the 

heart or extracranial arteries) or hemorrhagic (either 

subarachnoid or parenchymal). Many of the pathophysiologic mechanisms discussed in preceding 

sections for atherosclerosis and CHD also apply to cerebrovascular disease, particularly for ischemic stroke. 

The epidemiologic association between cigarette 

smoking and stroke is well established. The 1964 Surgeon General’s report summarized studies conducted 

in the 1950s describing the increase in mortality from 

strokes in smokers compared with nonsmokers 

(USDHEW 1964). Subsequent Surgeon General’s 

reports reviewed further evidence indicating that 

(1) smoking is clearly associated with an increase in 

both the incidence of and mortality from cerebrovascular disease; (2) smoking is associated with the risk 

of both ischemic stroke and subarachnoid hemorrhage; 

(3) the smoking-associated risk of stroke is particularly elevated in younger persons, and the smokingassociated risk of subarachnoid hemorrhage is elevated 

in women (USDHHS 1990); and (4) as with many other 

smoking-related diseases, later studies (e.g., CPS-II 

1982–1986) tend to show a higher RR of stroke in relation to smoking than did earlier studies (e.g., CPS-I 

1959–1965). These more recent findings may be 

explained by cohort effects related to smoking duration and earlier smoking initiation in birth cohorts who 

reached middle to older ages (Garfinkel and Stellman 

1988). 

Cardiovascular Diseases 393 
Surgeon General’s Report 

A meta-analysis reviewed 32 case-control and 

cohort studies and documented that cigarette smoking increased the risk of stroke by an estimated 50 percent, although the effect differs according to stroke 

subtype: the RR for ischemic stroke was 1.9, and 2.9 

for subarachnoid hemorrhage, but no elevation in risk 

was found for cerebral hemorrhage (Shinton and 

Beevers 1989). 

Based on the wealth of epidemiologic, biologic, 

and laboratory evidence available at the time, the 1989 

Surgeon General’s report concluded that there was a 

causal association between smoking and cerebrovascular disease (USDHHS 1989). Using estimates of 

prevalence and RR from the large CPS-II study, the 

report estimated that among persons younger than 65 

years of age, smoking was responsible for 51 percent 

of cerebrovascular disease deaths in men and 55 percent in women. 

The 1990 Surgeon General’s report on smoking 

cessation examined all previously published studies 

comparing the risk of stroke for lifetime nonsmokers 

with both current and former smokers (USDHHS 

1990). The report confirmed previous conclusions of a 

twofold to fourfold increase in risk associated with 

current smoking and concluded that the risk decreases 

steadily after smoking cessation, becoming indistinguishable in former smokers from that of lifetime nonsmokers after 5 to 15 years, depending on the study. 

Epidemiologic Evidence 

Both case-control and cohort studies published 

since the 1990 Surgeon General’s report have confirmed the epidemiologic association of cigarette smoking with the main subtypes of stroke (i.e., ischemic 

stroke and subarachnoid hemorrhage). One of the most 

important publications provides results from the British Doctors Study, reporting an association between 

smoking and stroke (among other disease outcomes) 

in more than 30,000 male British physicians followed 

for over 40 years, from 1951–1991 (Doll et al. 1994). 

These findings confirmed previous reports of a strong 

and consistent epidemiologic association between 

smoking and mortality from stroke subtypes. Compared with lifetime nonsmokers, current smokers at 

baseline had RRs of 1.31 for thrombotic stroke, 1.37 

for hemorrhagic stroke, and 2.14 for subarachnoid 

hemorrhage. Dose-response relationships with an increasing number of cigarettes smoked per day were 

reported for both thrombotic and hemorrhagic subtypes, and were particularly strong for subarachnoid 

hemorrhage (RR = 1.43, 1.71, and 3.43 for smokers of 

1–14, 15–24, and >24 cigarettes per day, respectively; 

p for trend <0.001). 

Another report addressed the association between smoking and stroke mortality in the Multiple 

Risk Factor Intervention Trial (MRFIT) (Kuller et al. 

1991). Among the more than 360,000 people initially 

screened, current smokers had a RR for overall stroke 

mortality of 2.5 (p <0.001) during a 10-year follow-up, 

with a clear dose-response relationship between an 

increased risk and an increase in the average number 

of cigarettes smoked per day. 

In addition to the risk for stroke mortality, other 

studies have reported on the effects of smoking on 

stroke incidence. Data from a 10-year follow-up of 

more than 22,000 participants in the United States Physicians Study showed that, compared with lifetime 

nonsmokers, current smokers of 1 to 19 cigarettes per 

day had an age-adjusted RR for stroke incidence of 

2.02 (95 percent CI, 1.23–3.31), and smokers of 20 or 

more cigarettes per day had an adjusted RR of 2.52 

(95 percent CI, 1.75–3.61; p for trend <0.0001) (Robbins 

et al. 1994). Similar dose-response associations between the amount smoked and stroke incidence 

were reported in the British Regional Heart Study, a 

population-based cohort study of about 7,700 middleaged men (Shaper et al. 1991). In subsequent analyses 

of this study (Wannamethee et al. 1995), stroke risks 

for former smokers fell to the lowest levels around five 

years after smoking cessation; the remaining risk levels depended on the amount smoked: former heavy 

smokers fell to a level similar to that of light smokers, 

and former light smokers fell to a level similar to that 

of lifetime nonsmokers. Switching to a pipe or cigar 

had little effect on risk. Benefits from smoking cessation were observed after controlling for all possible 

relevant confounders and were present in both normotensive and hypertensive persons, although the 

benefit seemed to be more marked in the latter group. 

This study also confirmed the conclusions of the 1990 

Surgeon General’s report on the benefits of smoking 

cessation on stroke risk (Wannamethee et al. 1995). 

The above studies were all conducted on men of 

mostly European origin. However, there is a wealth of 

evidence demonstrating that smoking is also associated with strokes in women and in all ethnic groups 

and countries where the hypothesis has been tested. 

In contrast to some earlier studies that suggested that 

the RR for stroke (especially subarachnoid hemorrhage) was more elevated in female smokers than in 

male smokers, recent cohort studies of a variety of 

population samples tend to show similar RRs in both 

men and women. In a large cohort study of more than 

394 Chapter 3 
The Health Consequences of Smoking 

42,000 participants in a health survey in Finland, RRs 

for the incidence of subarachnoid hemorrhage were 

2.4 (95 percent CI, 1.6–3.7) in men and 2.5 (95 percent 

CI, 1.5–4.1) in women, independent of other known 

stroke risk factors (i.e., age, hypertension, and body 

weight) (Knekt et al. 1991). Another issue of particular concern to women is the possible synergism between oral contraceptives and smoking on the risks of 

stroke. Whereas earlier studies suggested that possibility (Kannel 1987), it was recently argued that lowdose oral contraceptive combinations may not interact with smoking to substantially increase these risks 

(Mishell 1999). However, a report based on a large cohort of reproductive-aged women in the Kaiser 

Permanente study (Petitti et al. 1996), where 408 strokes 

were observed among 1.1 million women (>3.6 million person-years of observation), found that the RRs 

for ischemic stroke and for hemorrhagic stroke among 

current smokers compared with nonsmokers were 2.66 

(95 percent CI, 1.65–4.30) and 2.70 (95 percent CI, 1.71– 

4.27), respectively. The combination of smoking and 

low-dose oral contraceptives was associated with an 

overall stroke RR of 3.64 (95 percent CI, 0.95–13.87). 

Even though few studies have published ethnicor minority-specific data on the relationship between 

smoking and stroke risks, there is consistent evidence 

of an association in African Americans, a group with a 

particularly high risk for cerebrovascular disease 

(Gillum 1999). Furthermore, in ecologic analyses conducted with data from the World Health Organization’s MONICA (Multinational Monitoring of Trends 

and Determinants in Cardiovascular Disease) project, 

smoking and hypertension were the main factors explaining the variability of stroke mortality rates across 

populations (Stegmayr et al. 1997). Similar conclusions 

were reached in analyses based on persons from the 

multinational Seven Countries Study (Jacobs et al. 

1999). 

In a cohort study of a Korean population with 

low cholesterol levels, the risk for stroke was linearly 

associated with increasing amounts of cigarette smoking (Jee et al. 1999). Another large cohort study in an 

Asian population was conducted in a cohort of approximately 265,000 Japanese men and women 

(Hirayama 1990). The RRs for nonhemorrhagic strokes 

were only slightly elevated in current smokers compared with lifetime nonsmokers (1.08 in men and 1.18 

in women), whereas for subarachnoid hemorrhage the 

corresponding RRs were 1.82 and 1.71. 

The higher RRs for a subarachnoid hemorrhage 

compared with other stroke subtypes are consistent 

with the observations summarized in previous 

Surgeon General’s reports as well as in most recent 

studies. Among those screened for the MRFIT, the 

smoking-related RR for a nonhemorrhagic stroke was 

2.1, whereas the RR for a subarachnoid hemorrhage 

was 3.0 (Neaton et al. 1993). Teunissen and colleagues 

(1996) reviewed the data and consistently found smoking to be an independent risk factor for subarachnoid 

hemorrhage. The mechanisms for this increased risk 

are likely due to damage to the cerebral artery wall 

associated with one or more components of cigarette 

smoke (Weir et al. 1998). Cumulative damage to the 

arterial elastica layer can result in an aneurysmal dilatation, and the presence of this dilatation with the additional impact of smoking on vasoactivity, especially 

in the presence of hypertension, may create high risks 

for a hemorrhagic event. 

Most of the recent studies described in this section adjusted for risk factors that could possibly confound the association between smoking and stroke. 

From the epidemiologic standpoint, only hypertension 

appears as consistently related to stroke risks as smoking does. However, controlling for blood pressure or 

hypertension status has very little effect on the observed strength of the smoking-stroke association seen 

in most studies. This finding would be expected, given 

the weak and inverse relationship of smoking with 

hypertension. In the analysis by Thun and colleagues 

(2000) of the CPS-II cohort, the estimate of stroke 

deaths for the United States based on the age-adjusted 

risk estimate was 21,400. With adjustment for several 

potential confounding factors there was a slight drop 

to about 17,800. 

Evidence Synthesis 

The more recent evidence remains fully consistent with a causal effect of smoking on risk for cerebrovascular disease. The recent evidence extends the 

range of populations in which an association with 

smoking has been demonstrated and shows consistent 

associations of smoking with all major types of stroke. 

Conclusion 

1.	 The evidence is sufficient to infer a causal relationship between smoking and stroke. 

Implication 

Cigarette smoking remains a major cause of 

stroke in the United States. 

Cardiovascular Diseases 395 
Surgeon General’s Report 

Smoking and Abdominal Aortic Aneurysm 

Aortic aneurysm refers to the dilatation or expansion of the aorta between the arch and the division into the iliac arteries, while AAA occurs in the 

abdominal portion of the aorta. The aorta has a high 

pressure across its wall and rupture can quickly lead 

to death. Most AAAs are the result of atherosclerosis, 

although other conditions can cause them (Davies 

1998). Evidence of pathogenesis includes atherosclerosis, degradation of elastin in the aorta’s wall, and 

inflammation (Blanchard 1999). In the young trauma 

victims in the PDAY study, smoking was associated 

with the extent of atherosclerosis in the abdominal 

aorta (McGill et al. 2001). In the smaller sample from 

the Bogalusa Heart Study, the findings were similar 

(Berenson et al. 1998). The natural progression of AAAs 

is to grow increasingly larger, and when they become 

greater than 4 cm in diameter there is a substantial risk 

for rupture. Most persons do not have any symptoms 

until the aneurysm ruptures; at that point, sudden 

death can occur. Surgical repair is much less successful once the aneurysm begins to leak. Estimates for 

2003 were that AAAs caused more than 15,000 deaths 

and 60,000 hospitalizations in the United States (AHA 

2002). 

Epidemiologic Evidence 

Evidence linking tobacco smoking and aortic atherosclerosis has been available for several decades 

(Table 3.7). In 1983, the Surgeon General’s report 

suggested that cigarette smoking aggravates or accelerates aortic atherosclerosis (USDHHS 1983), and several epidemiologic studies indicated that smokers had 

elevated death rates from ruptured abdominal aneurysms compared with nonsmokers. A literature review 

published in 1999 found a positive, strong, and independent association between smoking and AAA in 10 

studies of cohort, case-control, and cross-sectional designs (Blanchard 1999). 

The findings of the long-term cohort studies provide clear evidence for an association of smoking with 

AAA. During the 40 years of follow-up of the British 

physicians cohort, the risk for death from AAA was 

increased more than fourfold in current smokers compared with lifetime nonsmokers and was increased 

twofold in former smokers (Doll et al. 1994). In the 

U.S. veterans cohort, there was a fivefold increase for 

current smokers and a more than doubling of mortality for this cause of death in former smokers (Rogot 

and Murray 1980). In CPS-I, the increased risk for current smokers was of a similar magnitude (Burns et al. 

1997). 

Recent studies not included in the 1999 review 

also confirm this association. For example, in a casecontrol study using state-of-the-art clinical and epidemiologic methods (Blanchard et al. 2000), smoking was 

strongly associated with AAA with adjustment for all 

known risk factors. A dose-response relationship was 

evident. Compared with lifetime nonsmokers, the adjusted OR was 2.75 (95 percent CI, 0.85–8.91) for 1 to 

19 pack-years, 7.31 (95 percent CI, 2.44–21.9) for 20 to 

34 pack-years, 7.35 (95 percent CI, 2.40–22.5) for 35 to 

49 pack-years, and 9.55 (95 percent CI, 2.81–32.5) for 

50 or more pack-years. Other recent case-control studies have also found dose-response relationships 

(Wilmink et al. 1999), as have earlier cohort studies. 

As in other cohort studies published in recent 

years, the Edinburgh Artery Study, a population-based 

cohort study of men and women 55 through 74 years 

of age, found that current (or recent) smoking also was 

strongly associated with AAA (OR = 3.1 [95 percent 

CI, 1.5–6.2]) (Lee et al. 1997). This association can be 

partially explained by atherosclerosis (Reed et al. 1992), 

although cohort data from the Edinburgh Artery Study 

suggest an increased risk for aortic aneurysm associated with smoking beyond that from underlying atherosclerosis (Lee et al. 1997). Lee and colleagues (1997) 

found that smoking remained associated with a risk 

for incident aneurysm after adjusting for CVD and the 

AAI at baseline. In a cohort of Finnish males, risk for 

AAA was positively associated with the number of 

years of smoking (Törnwall et al. 2001) and with the 

number of cigarettes smoked in a 33-year cohort study 

in Sweden (Nilsson et al. 2001). 

The CHS is a multicenter prospective cohort 

study of cardiovascular disease in older Americans 

(Alcorn et al. 1996). In the fifth year of follow-up, ultrasound was used to evaluate the abdominal aortas 

of all participants. The prevalence rates for aneurysm 

by smoking were 6.8 percent, 11.5 percent, and 14.4 

percent for never, former, and current smokers, respectively. 

396 Chapter 3 
The Health Consequences of Smoking 

Evidence Synthesis 

Smoking causes atherosclerosis in arteries, including the abdominal aorta. Autopsy studies show 

that even young adults who smoke have more plaque 

in their aortas than do lifetime nonsmokers. Other 

mechanisms by which smoking might injure the abdominal aorta include inflammation and damage to 

elastin. 

The epidemiologic evidence, coming from multiple studies of differing design and location, shows a 

strong association of smoking with risk for AAA. Doseresponse relationships with the amount and duration 

of smoking have been reported and risks are lower in 

former than in current smokers. Uncontrolled confounding cannot explain the findings. 

Summary 

Conclusion 

1.	 The evidence is sufficient to infer a causal relationship between smoking and abdominal aortic 

aneurysm. 

Implication 

Smoking is one of the few currently avoidable 

causes of this frequently fatal disease. 

Research during the past decade has produced 

further evidence that tobacco smoking is causally related to all of the major clinical cardiovascular diseases. 

A large body of evidence coming from multiple populations, age groups, and both genders outlined in previous Surgeon General’s reports indicates that tobacco 

smoking causes atherosclerosis and associated clinical syndromes. A dose-response relationship has been 

repeatedly demonstrated with higher levels of cigarette smoking and a longer duration of smoking. Evidence now suggests that light smokers (fewer than 10 

cigarettes per day) have moderate but measurable increases in the risks for CVD, and passive smoking has 

been causally associated with CHD (California Environmental Protection Agency 1997; Scientific Committee on Tobacco and Health 1998). New evidence also 

documents that tobacco smoking is associated with 

subclinical or very early atherosclerosis. Multiple potential confounding factors have been considered, and 

none account for the association between tobacco 

smoking and CVD. Most large prospective studies of 

the association between smoking and cardiovascular 

outcomes conducted in recent years controlled for 

other known cardiovascular risk factors that could be 

proposed as possible confounders (e.g., diet, physical 

exercise, BMI, and other lifestyle habits). 

The temporal relationship between tobacco 

smoking and CVD has never been in doubt due to the 

extensive data from carefully conducted prospective 

cohort studies. A large body of research documents 

the impact of tobacco smoke on a wide range of biologic processes related to atherosclerosis, establishing 

biologic plausibility. New evidence also documents 

that tobacco smoking is associated with subclinical atherosclerosis (i.e., with the presence of atherosclerosis) 

earlier in its natural history, before it manifests clinically. The cross-sectional and prospective evidence 

summarized in this chapter consistently demonstrates 

that tobacco smoking is related to the thickness of the 

intimal-medial layers of the carotid and popliteal arteries as well as to the presence of coronary atherosclerosis (by angiographic and pathology studies) and 

subclinical markers of cerebrovascular disease (white 

matter disease and subclinical infarcts). This conclusion is entirely consistent with the strong evidence 

linking tobacco smoking and clinical cardiovascular 

disease manifestations as reviewed in this and in 

previous Surgeon General’s reports. Atherosclerosis is 

a complex disease process that progresses slowly 

across different vascular beds and involves multiple 

metabolic, inflammatory, and homeostatic pathways. 

Cardiovascular Diseases 397 
Surgeon General’s Report 

Table 3.7 Studies on the association between smoking and the risk of abdominal aortic aneurysm (AAA) 

Study Design/population Tobacco exposure Outcome 

Kahn 1966 U.S. veterans cohort study 

293,658 persons aged 31–84 years 

(mainly white male World War I 

[WWI] veterans) who held active 

U.S. government life insurance policies 

in December 1953 

Questionnaires were administered in 

1954 and 1957 with 198,834 and 49,361 

responses, respectively 

8.5 years of follow-up 

United States (nationwide) 

• Cigarettes/day 

• Pipes and cigars 

only 

Death from 

nonsyphilitic 

aneurysm of the 

aorta 

Weir and 

Dunn 1970 

Cohort study 

68,153 men aged 35–64 years 

482,658 person-years of observation 

California 

Began in 1954 

• Nonsmokers/all 

smokers 

• Packs/day 

Death from aortic 

aneurysm 

Rogot and 

Murray 1980 

U.S. veterans cohort study (update) 

293,658 persons aged 31–84 years 

(mainly white male WWI veterans) 

who held active U.S. government life 

insurance policies in December 1953 

Questionnaires were administered in 

1954 and 1957 with 198,834 and 49,361 

responses, respectively 

16 years of follow-up 

United States (nationwide) 

• Never smoked 

• Former cigarette 

smokers 

• Current cigarette 

smokers 

• Cigarettes/day 

• Cigars only 

• Pipes only 

Death from aortic 

aneurysm 

Strachan 

1991 

Whitehall Cohort Study of 18,403 male 

civil servants examined at the ages of 

40–64 years 

18-year follow-up 

England 

• Nonsmokers 

• Manufactured 

cigarettes 

• Hand-rolled 

cigarettes 

• Pipes or cigars only 

Death from aortic 

aneurysm 

*CI = Confidence interval. 

†

RR = Relative risk. 

398 Chapter 3 
Table 2aa Endometrial Cancer Studies

The Health Consequences of Smoking 

Findings Risk estimates (95% CI*) Comments 

• Significant mortality 

rate for current and 

former cigarette 

smokers (greater than 

expected) 

• Dose-response relationship was observed 

Mortality ratios 

Total current smokers 5.15 (significant) 

10–20 cigarettes/day 5.58 (significant) 

21–30 cigarettes/day 6.55 (significant) 

Current pipe and cigar 1.76 

smokers only 

Former cigarette smokers 2.75 (significant) 

Never smokers were the 

comparison group; age 

distributions were standardized using the 1960 distribution of the U.S. male population by single years; p values 

and 95% CIs were not 

provided 

• Increased risk was 

associated with 

cigarette smoking 

RR† 

Nonsmokers 1.0 (referent) 

All smokers 2.64 

About 1/2 pack or less 2.44 

About 1 pack 2.88 

About 1 1/2 or more packs 2.54 

Nonsmokers included pipe 

and cigar smokers; p values 

and 95% CIs were not 

provided 

• Dose-response relationship was observed 

with more cigarettes/ 

day 

Mortality ratios 

Former cigarette smokers 2.58 

All current cigarette smokers 5.23 

<10 cigarettes/day 2.29 

10–20 cigarettes/day 5.46 

21–39 cigarettes/day 6.36 

40 cigarettes/day 7.18 

Cigars only 2.04 

Pipes only 2.07 

Never smokers were the 

comparison group; p values 

and 95% CIs were not 

provided 

• 99 outcome events 

• All forms of tobacco 

use in this study were 

associated with 

increased mortality 

rates 

Mortality ratios 

Manufactured cigarettes 5.3 (3.1–9.1) 

Hand-rolled cigarettes 20.1 (9.2–43.8) 

Pipes or cigars only 5.4 (1.9–15.3) 

Mortality ratios were calculated against nonsmokers 

at entry; mortality ratios were 

adjusted for diastolic blood 

pressure, and were adjusted 

by analysis of matched sets 

using conditional logistic 

regression 

Cardiovascular Diseases 399 
Surgeon General’s Report 

Table 3.7 Continued 

Study Design/population Tobacco exposure Outcome 

Doll et al. 

1994 

Cohort study 

34,439 British male doctors who replied 

to a postal questionnaire in 1951 

United Kingdom 

1951–1991 

• Nonsmokers 

• Former smokers 

• Current smokers 

• Cigarettes/day 

Death from aortic 

aneurysm 

Alcorn et al. 

1996 

Cross-sectional study 

656 persons aged 65–90 years 

from a Pittsburgh subgroup of the 

Cardiovascular Health Study 

Pittsburgh 

1990–1992 

• Never smoked 

• Former smokers 

• Current smokers 

AAA was defined 

as an infrarenal 

aortic diameter 

3 cm, an infrarenal 

to suprarenal 

diameter ratio 1.2, 

or a history of AAA 

repair 

Powell et al. 

1996 

Screening cross-sectional study of 

patients with peripheral arterial disease 

44 AAA patients 

244 hospital controls matched for age 

and gender 

London 

1989–1992 

• Pack-years‡ 

• Cigarettes/day 

NR§ 

‡

Pack-years = The number of years of smoking multiplied by the number of packs of cigarettes smoked per day.
 §

NR = Data were not reported.
 

OR = Odds ratio.
 

400 Chapter 3 
Table 2aa Endometrial Cancer Studies

The Health Consequences of Smoking 

Findings Risk estimates (95% CI) Comments 

• Significant association; p <0.001 for 

trend 

• AAAs were more 

prevalent among 

smokers 

• Pack-years p value 

for trend = 0.174 

• Cigarettes/day 

p value for trend = 

0.008 

• No association was 

found between AAA 

risk and type of 

tobacco used 

Annual mortality per 100,000 men 

Nonsmokers 15 

Former smokers 33 

Current smokers 62 

1–14 cigarettes/day 38 

15–24 cigarettes/day 74 

25 cigarettes/day 81 

Prevalence among those with AAA 

Never smoked 6.8% 

Former smokers 11.5% 

Current smokers 14.4% 

p value for trend <0.0001 

ORΔ 

<35 pack-years 1.0 (referent) 

35–55 pack-years 2.07 (0.95–4.52) 

>55 pack-years 1.84 (0.61–3.42) 

0–10 cigarettes/day 1.0 (referent) 

11–20 cigarettes/day 3.03 (1.29–7.22) 

21 cigarettes/day 1.99 (0.97–3.73) 

Mortality rates were standardized for age and calendar 

period 

p values were calculated 

using logistic regression and 

were adjusted for age, gender, 

height, and weight 

Matched analyses were 

carried out using conditional 

logistic regression 

Cardiovascular Diseases 401 
Surgeon General’s Report 

Table 3.7 Continued 

Study 

Burns et al. 

1997 

Design/population 

Cohort study 

Cancer Prevention Study I 

Approximately 68,000 American Cancer 

Society volunteers 

Questionnaires administered: 1959– 

1960, 1961, 1963, 1965, and 1972 

United States (nationwide) 

1959–1972 

Tobacco exposure 

• Cigarettes/day 

stratified by age 

Outcome 

Death from aortic 

aneurysm 

Hrubec and 

McLaughlin 

1997 

U.S. veterans cohort study 

293,658 persons aged 31–84 years 

(mainly white male WWI veterans) 

who held active U.S. government life 

insurance policies in December 1953 

Questionnaires were administered in 

1954 and 1957 with 198,834 and 49,361 

responses, respectively 

26-year follow-up (1954–1980) 

United States (nationwide) 

• Former regular 

cigarette smokers 

Death from aortic 

aneurysm 

402 Chapter 3 
Table 2aa Endometrial Cancer Studies

The Health Consequences of Smoking 

Findings Risk estimates (95% CI) Comments 

• For men, there was 

a dose-response 

relationship in every 

age category 

Mortality risk ratios 

Men 

Aged 50–64 years 

1–19 cigarettes/day 3.1 

20 cigarettes/day 4.2 

21 cigarettes/day 5.3 

Aged 65–79 years 

1–19 cigarettes/day 4.4 

20 cigarettes/day 6.1 

21 cigarettes/day 8.2 

Aged 80 years 

1–19 cigarettes/day 3.0 

20 cigarettes/day 3.9 

21 cigarettes/day 4.5 

Women 

Aged 35–49 years 

1–19 cigarettes/day 6.2 

20 cigarettes/day 6.1
 

21 cigarettes/day NR
 

Aged 50–64 years 

1–19 cigarettes/day 3.4 

20 cigarettes/day 7.5 

21 cigarettes/day 12.4 

Aged 65–79 years 

1–19 cigarettes/day 2.4 

20 cigarettes/day 4.4 

21 cigarettes/day 1.4 

Aged 80 years 

1–19 cigarettes/day 4.5 

20 cigarettes/day 4.2
 

21 cigarettes/day NR
 

None 

• Significant risk was 

associated with 

former regular 

smoking 

RR 

Never regular smokers 1.0 (referent) 

Former regular smokers 2.6 (2.2–3.1) 

RR was calculated using 

Poisson regressions 

Cardiovascular Diseases 403 
Surgeon General’s Report 

Table 3.7 Continued 

Study Design/population Tobacco exposure Outcome 

Wilmink et 

al. 1999 

Nested case-control study 

From a population-based screening 

program for AAA 

Men aged >50 years 

210 cases (infrarenal aortic diameter 

>29 mm) 

237 controls 

Huntington, United Kingdom 

• Duration of 

smoking 

• Cigarettes/day 

NR 

Blanchard 

et al. 2000 

Case-control study 

98 incident diagnoses of AAA 

102 hospital controls 

Winnipeg, Manitoba (Canada) 

1992–1995 

• Pack-years NR 

Nilsson et 

al. 2001 

Cohort study 

Questionnaire replies from 16,458 men 

and 25,086 women aged 18–69 years, 

chosen from the 1960 census population 

Analysis was done in 1996 

Sweden 

1963 

• Never smoked 

• Former smokers 

• Current smokers 

Death from aortic 

aneurysm 

404 Chapter 3 
Findings Risk estimates (95% CI) Comments 

• When cigarettes/day 

ORs were adjusted 

for duration of 

smoking, associations 

became insignificant 

Duration of smoking OR

0 years 1.0 (referent) 

 20 years 1.4 (0.6–3.4)

21–40 years 3.6 (1.6–8.2)

>40 years 5.8 (2.6–13.0) 

Cigarettes/day OR

0 cigarettes/day 1.0 (referent)

1–5 cigarettes/day 2.1 (0.7–6.1)

6–10 cigarettes/day 5.1 (2.0–13.0)

11–15 cigarettes/day 3.4 (1.3–8.8)

16–20 cigarettes/day 4.2 (1.7–10.5)

>20 cigarettes/day 7.0 (2.7–18.0) 

ORs were calculated using 

multivariate unconditional 

regression and were adjusted 

for age, family history of 

AAA, history of ischemic 

heart disease and treated 

hypertension, and the presence of peripheral arterial 

occlusive disease 

• Smoking was significantly associated with 

AAA in women but 

not in men 

Men OR

1–19 pack-years 1.21 (0.22–6.66)

20–34 pack-years 2.45 (0.51–11.7)

35–49 pack-years 2.96 (0.63–14.0) 

 50 pack-years 3.83 (0.84–17.5) 

Women OR

1–19 pack-years 5.81 (0.95–35.5)

20–34 pack-years 21.7 (3.87–121.5)

35–49 pack-years 18.2 (3.01–110.5) 

 50 pack-years 28.9 (2.30–362.1) 

ORs were calculated using 

unconditional logistic 

regression; risk estimates were 

adjusted for age, diastolic 

blood pressure, diabetes 

mellitus status, and family 

history of AAA 

• Risk associated with 

current smoking was 

significant for both 

men and women 

Men RR

Never smoked 1.00 (referent)

Former smokers 1.57 (0.94–2.63)

Current smokers 3.30 (2.08–5.23) 

Women RR

Never smoked 1.00 (referent)

Former smokers 0.42 (0.06–3.02)

Current smokers 3.43 (2.11–5.59) 

RRs were calculated using 

Cox proportional hazards 

regression model; risk estimates were adjusted for age 

and place of residence 

Table 2aa Endometrial Cancer Studies

The Health Consequences of Smoking 

Cardiovascular Diseases 405 
Surgeon General’s Report 

Table 3.7 Continued 

Study Design/population Tobacco exposure Outcome 

Törnwall et 

al. 2001 

Cohort study 

29,133 male smokers aged 50–69 years 

Participants in an alpha-tocopherol, 

beta-carotene cancer prevention study 

Enrollment: 1985–1993 

Ended: spring 1993 

Finland 

• Cigarettes/day 

• Duration of 

smoking 

AAA, ruptured 

or unruptured 

American 

Cancer 

Society, 

unpublished 

data, 2002 

Cohort study 

Cancer Prevention Study II (CPS-II) 

Approximately 77,000 American Cancer 

Society volunteers 

Initial questionnaire: 1982 

United States (nationwide and Puerto 

Rico) 

• Nonsmokers 

• Former cigarette 

smokers 

• Current cigarette 

smokers 

Death from aortic 

aneurysm 

As reviewed above, there is very strong evidence from 

animal and laboratory experiments documenting the 

potential for tobacco products to have multiple detrimental effects at different stages of the natural history 

of atherosclerosis, both in its subclinical evolution 

and in the precipitation of its clinical manifestations. 

The new conclusion regarding tobacco smoking 

and heart disease in this report relates to subclinical 

disease. 

406 Chapter 3 
Table 2aa Endometrial Cancer Studies

The Health Consequences of Smoking 

Findings Risk estimates (95% CI) Comments 

• 181 outcome events 

• Duration of smoking 

was a stronger risk 

factor than cigarettes/ 

day 

Cigarettes/day RR 

 14 cigarettes/day 1.00 (referent)

15–24 cigarettes/day 1.01 (0.70–1.46) 

 25 cigarettes/day 0.81 (0.52–1.27) 

Duration of smoking RR 

 32 years 1.00 (referent)

33–40 years 1.45 (0.88–2.39)

>40 years 2.25 (1.33–3.81) 

RRs were calculated using 

Cox proportional hazards 

model; comparisons were 

limited to smokers only; 

risk estimates were adjusted 

for age, body mass index, 

systolic blood pressure, 

diastolic blood pressure, 

serum total cholesterol, 

serum high-density lipoprotein cholesterol, serum alphatocopherol, serum betacarotene, total energy intake, 

alcohol consumption, history 

of diabetes mellitus, education, and exercise performed 

in leisure time 

• 1,275 outcome events 

in men 

• 413 outcome events in 

women 

• Significantly increased 

mortality among both 

men and women who 

were current cigarette 

smokers 

Death rate ratios 

Men

Nonsmokers 1.00 (referent)

Former smokers 2.42 (2.03–2.88)

Current smokers 5.97 (5.03–7.09) 

Women

Nonsmokers 1.00 (referent)

Former smokers 1.81 (1.41–2.32)

 Current smokers 6.82 (5.66–8.22) 

Death rates were standardized to the CPS-II population 

Conclusions
 

Smoking and Subclinical Atherosclerosis 

1.	 The evidence is sufficient to infer a causal relationship between smoking and subclinical 

atherosclerosis. 

Smoking and Coronary Heart Disease 

2.	 The evidence is sufficient to infer a causal relationship between smoking and coronary heart disease. 

3.	 The evidence suggests only a weak relationship 

between the type of cigarette smoked and coronary heart disease risk. 

Smoking and Cerebrovascular Disease 

4.	 The evidence is sufficient to infer a causal relationship between smoking and stroke. 

Smoking and Abdominal Aortic Aneurysm 

5.	 The evidence is sufficient to infer a causal relationship between smoking and abdominal aortic 

aneurysm. 

Cardiovascular Diseases 407 
Surgeon General’s Report 

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